Rho kinase inhibitors

ABSTRACT

A compound represented by the formula (1): 
                         
wherein R 1 —X— indicates that 1 to 4 R 1 —X— groups are present which may be the same or different,
         the ring A is a saturated or unsaturated 5-membered heterocyclic ring,   X is a single bond, a group represented by the formula: —N(R 3 )—, —O— or —S—, or the like.   R 1  is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like,   R 2  is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, and   R 3  is a hydrogen atom, a substituted or unsubstituted alkyl group, or the like;
 
a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug is a useful compound as a therapeutic agent for diseases for which Rho kinase is responsible.

This application is a 371 of PCT/JP02/0589 filed on Jun. 6, 2002.

TECHNICAL FIELD

The present invention relates to a Rho kinase inhibitor (ROCK-IIinhibitor, ROCα inhibitor) containing a novel fused heterocyclic ringcompound, a prodrug thereof or a pharmaceutically acceptable salt ofsaid compound or prodrug.

It is known that Rho kinase participates in vasoconstriction, plateletaggregation, bronchial smooth muscle constriction, vascular smoothmuscle proliferation•emigration, endothelial proliferation•emigration,stress fiber formation, cardiac hypertrophy, Na/H exchange transportsystem activation, adducin activation, ocular hypertension, erectiledysfunction, premature birth, retinopathy, inflammation, immunediseases, AIDS, fertilization and implantation of fertilized ovum,osteoporosis, brain functional disorder, infection of digestive tractswith bacteria, and the like.

The compound of the present invention has inhibitory effect on Rhokinase and is useful as a therapeutic agent for diseases which are suchthat morbidity due to them is expected to be improved by inhibition ofRho kinase and secondary effects such as inhibition of the Na⁺/H⁺exchange transport system caused by the Rho kinase inhibition, forexample, hypertension, peripheral circulatory disorder, angina, cerebralvasospasm, premature birth, and asthma, which are improved by smoothmuscle relaxing effect, and diseases (chronic arterial obstruction andcerebrovascular accident) caused by hyperaggregability of platelet;diseases such as arteriosclerosis, fibroid lung, fibroid liver, liverfailure, fibroid kidney, renal glomerulosclerosis, kidney failure, organhypertrophy, prostatic hypertrophy, complications of diabetes, bloodvessel restenosis, and cancer, which are improved by inhibitory effecton cell over-proliferation•emigration•fibrosing (e.g. fibroblastproliferation, smooth muscle cell proliferation, mesangial cellproliferation and hemoendothelial cell proliferation); cardiachypertrophy; heart failure, ischemic diseases; inflammation; autoimmunediseases; AIDS; fertilization and implantation of fertilized ovum;osteopathias such as osteoporosis; brain functional disorder; infectionof digestive tracts with bacteria; sepsis; adult respiratory distresssyndrome; retinopathy; glaucoma; and erectile dysfunction.

BACKGROUND ART

As compounds having inhibitory activity against Rho kinase, there areexemplified the compounds disclosed in International Patent Laid-OpenNos. WO98/06433, WO99/64011 and WO00/57914.

DISCLOSURE OF THE INVENTION

A problem to be solved by the present invention is to find a compoundthat has inhibitory activity against Rho kinase and is useful as atherapeutic agent for the diseases described above.

The present inventors earnestly investigated in order to solve the aboveproblem, and consequently found that the following compound, a prodrugthereof or a pharmaceutically acceptable salt of said compound orprodrug (they are hereinafter abbreviated as the compound of the presentinvention if necessary) has an excellent inhibitory effect against Rhokinase. Moreover, the present inventors found that the compound havinginhibitory effect against Rho kinase suppresses the constriction of thedetrusor of bladder and is useful as a prophylactic or therapeutic agentfor urinary incontinence. That is, the present invention relates to thefollowing.

-   -   [1] A Rho kinase inhibitor comprising a compound represented by        the formula (1):

wherein R¹—X— indicates that 1 to 4 R¹—X— groups are present which maybe the same or different,

the ring A is a saturated or unsaturated 5-membered heterocyclic ring,

X is a single bond, a group represented by the formula: —O—, —N(R³)—,—N(R³)C(═O)—, —C(═O)N(R³)—, —S(O)_(n)—, —N(R³)S(O)₂—, —S(O)₂N(R³)— or—C(═O)—, or a substituted or unsubstituted alkylene group (the —CH₂—group of said alkylene group may be substituted by one or more groupswhich may be the same or different and are selected from groupsrepresented by the formula: —O—, —N(R⁴)—, —N(R⁴)C(═O)—, —C(═O)N(R⁴)—,—S(O)_(n)—, —N(R⁴)S(O)₂—, —S(O)₂N(R⁴)— or —C(═O)—, and any two adjacentcarbon atoms of said alkylene group may form a double bond or a triplebond),

n is 0, 1 or 2,

R¹ is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group,a cyano group, a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted alkoxycarbonyl group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted acyl group, a substituted or unsubstituted alkylsulfonylgroup, a substituted or unsubstituted arylsulfonyl group, or acycloalkyl group substituted by a substituted or unsubstituted alkylgroup,

R² is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group,a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted alkoxycarbonyl group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted acyl group, or a group represented by the formula: —OR⁸,—N(R⁹)R¹⁰, —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or —S(O)_(m)R¹¹, provided that inthe case of R² being a substituent on a nitrogen atom, R² is a hydrogenatom, a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted alkoxycarbonyl group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted acyl group, or a group represented by the formula:—CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or —S(O)_(m)R¹¹,

each of R³ and R⁴, which may be the same or different, is a hydrogenatom, a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted aromatic group, asubstituted or unsubstituted arylalkyl group, or a substituted orunsubstituted acyl group,

m is 0, 1 or 2,

each of R⁸, R⁹ and R¹⁰, which may be the same or different, is ahydrogen atom, a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted alkoxycarbonyl group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted acyl group, or a substituted or unsubstituted arylalkylgroup, or R⁹ and R¹⁰, when taken together with the nitrogen atom towhich they are bonded, form a substituted or unsubstituted saturated 5-to 8-membered cyclic amino group which may contain another heteroatom,and

R¹¹ is a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted aromatic group, or asubstituted or unsubstituted arylalkyl group, a prodrug of saidcompound, or a pharmaceutically acceptable salt of said compound orprodrug.

-   -   [2] A Rho kinase inhibitor according to [1], which is        represented by the formula (2):

wherein R¹—X— indicates that 1 to 4 R¹—X— groups are present which maybe the same or different,

X and R¹ are as defined in [1],

R⁵ is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group,a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted alkoxycarbonyl group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted acyl group, or a group represented by the formula: —OR⁸,—N(R⁹)R¹⁰, —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or —S(O)_(m)R¹¹,

R⁶ is a hydrogen atom, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstitutedsaturated heterocyclic group, a substituted or unsubstitutedalkoxycarbonyl group, a substituted or unsubstituted aromatic group, asubstituted or unsubstituted acyl group, or a group represented by theformula: —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or —S(O)_(m)R¹¹, and

R⁸, R⁹, R¹⁰, R¹¹ and m are as defined in [1].

-   -   [3] A Rho kinase inhibitor according to [1] or [2], wherein X is        a group represented by the formula: —N(R³)—.    -   [4] A Rho kinase inhibitor according to [1] or [2], wherein X is        a group represented by the formula: —N(R³)C(═O)—.    -   [5] A Rho kinase inhibitor according to [1] or [2], wherein X is        a group represented by the formula: —C(═O)N(R³)—.    -   [6] A Rho kinase inhibitor according to [1] or [2], wherein X is        a group represented by the formula: —O—.    -   [7] A Rho kinase inhibitor according to any one of [1] to [6],        wherein R¹ is a substituted or unsubstituted cycloalkyl group,        or a substituted or unsubstituted saturated heterocyclic group.    -   [8] A Rho kinase inhibitor according to [7], wherein the        saturated heterocyclic group is a substituted or unsubstituted        piperidinyl group, or a substituted or unsubstituted        tetrahydropyranyl group.    -   [9] A Rho kinase inhibitor according to any one of [1] to [6],        which is a therapeutic agent for hypertension, peripheral        circulatory disorder, angina, cerebral vasospasm, premature        birth, asthma, cerebrovascular accident, arteriosclerosis,        fibroid lung, fibroid liver, fibroid kidney, renal        glomerulosclerosis, kidney failure, prostatic hypertrophy,        complications of diabetes, blood vessel restenosis, cancer,        cardiac hypertrophy, heart failure, ischemic diseases,        inflammation, autoimmune diseases, AIDS, fertilization and        implantation of fertilized ovum, osteopathias, brain functional        disorder, infection of digestive tracts with bacteria, sepsis,        adult respiratory distress syndrome, retinopathy, glaucoma, or        erectile dysfunction.    -   [10] A compound represented by the formula (3):

wherein R¹—X— indicates that 1 to 4 R¹—X— groups are present which maybe the same or different,

X is a single bond, a group represented by the formula: —O—, —N(R³)—,—N(R³)C(═O)—, —C(═O)N(R³)—, —S(O)_(n)—, —N(R³)S(O)₂—, —S(O)₂N(R³)— or—C(═O)—, or a substituted or unsubstituted alkylene group (the —CH₂—group of said alkylene group may be substituted by one or more groupswhich may be the same or different and are selected from groupsrepresented by the formula: —O—, —N(R⁴)—, —N(R⁴)C(═O)—, —C(═O)N(R⁴)—,—S(O)_(n)—, —N(R⁴)S(O)₂—, —S(O)₂N(R⁴)— or —C(═O)—, and any two adjacentcarbon atoms of said alkylene group may form a double bond or a triplebond),

n is 0, 1 or 2,

Y¹ is a group represented by the formula: —C(R⁵¹)═ or a nitrogen atom,Y² is a group represented by the formula: —C(R⁵²)— or a nitrogen atom,Y³ is a group represented by the formula: —N(R⁶)— or an oxygen atom,

R¹ is a hydrogen atom, a halogen atom, a carboxyl group, a cyano group,a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted alkoxycarbonyl group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted acyl group, a substituted or unsubstituted alkylsulfonylgroup, a substituted or unsubstituted arylsulfonyl group, or acycloalkyl group substituted by a substituted or unsubstituted alkylgroup,

each of R³ and R⁴, which may be the same or different, is a hydrogenatom, a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted aromatic group, asubstituted or unsubstituted arylalkyl group, or a substituted orunsubstituted acyl group,

each of R⁵¹ and R⁵², which may be the same or different, is a hydrogenatom, a halogen atom, a nitro group, a carboxyl group, a substituted orunsubstituted alkyl group, a substituted or unsubstituted cycloalkylgroup, a substituted or unsubstituted cycloalkenyl group, a substitutedor unsubstituted saturated heterocyclic group, a substituted orunsubstituted alkoxycarbonyl group, a substituted or unsubstitutedaromatic group, a substituted or unsubstituted acyl group, or a grouprepresented by the formula: —OR⁸, —N(R⁹)R¹⁰, —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰or —S(O)_(m)R¹¹,

m is 0, 1 or 2,

each of R⁸, R⁹ and R¹⁰, which may be the same or different, is ahydrogen atom, a substituted or unsubstituted alkyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted alkoxycarbonyl group,a substituted or unsubstituted aromatic group, a substituted orunsubstituted acyl group, or a substituted or unsubstituted arylalkylgroup, or R⁹ and R¹⁰, when taken together with the nitrogen atom towhich they are bonded, form a substituted or unsubstituted saturated 5-to 8-membered cyclic amino group which may contain another heteroatom,

R¹¹ is a substituted or unsubstituted alkyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted saturatedheterocyclic group, a substituted or unsubstituted aromatic group, or asubstituted or unsubstituted arylalkyl group, and

R⁶ is a hydrogen atom, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstitutedsaturated heterocyclic group, a substituted or unsubstitutedalkoxycarbonyl group, a substituted or unsubstituted aromatic group, asubstituted or unsubstituted acyl group, or a group represented by theformula: —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or —S(O)_(m)R¹¹,

provided that when only one R¹—X— group is present, the followingcompounds are excluded:

-   -   (1) compounds in which X is a single bond and R¹ is a hydrogen        atom, a carboxyl group or an alkoxycarbonyl group,    -   (2) compounds in which X is a group represented by the formula:        —O—, and R¹ is a hydrogen atom, an unsubstituted alkyl group, an        alkyl group substituted by a carboxyl group, an unsubstituted        benzoyl group, or an unsubstituted benzyl group,    -   (3) compounds in which X is a group represented by the formula:        —NH—, and R¹ is a hydrogen atom or an amino-substituted alkyl        group.    -   (4) compounds in which X is a group represented by the formula:        —C(═O)—, and R¹ is a hydrogen atom,    -   (5) compounds in which X is a group represented by the formula:        —NHC(═O)—, and R¹ is an alkyl group or an unsubstituted benzyl        group, and    -   (6) compounds in which X is an unsubstituted alkylene group        (said alkylene group is not substituted by a group represented        by the formula: —O—, —N(R⁴)—, —N(R⁴)C(═O)—, —C(═O)N(R⁴)—,        —S(O)_(n)—, —N(R⁴)S(O)₂—, —S(O)₂N(R⁴)— or —C(═O)—), and R¹ is a        hydrogen atom or an unsubstituted amino group, a prodrug of said        compound or a pharmaceutically acceptable salt of said compound        or prodrug.    -   [11] A compound according to [10], which is represented by the        formula (4):

wherein X, R¹, R⁵¹ and R⁶ are as defined in [10],

a prodrug thereof or a pharmaceutically acceptable salt of the compoundor prodrug.

-   -   [12] A compound according to [10], which is represented by the        formula (5):

wherein R⁵¹ and R⁶ are as defined in [10],

X^(a), X^(b), X^(c) and X^(d) are independently the same as X defined in[10], and

R^(1a), R^(1b), R^(1c) and R^(1d) are independently a hydrogen atom, acarboxyl group, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkenyl group, a substituted or unsubstitutedsaturated heterocyclic group, a substituted or unsubstitutedalkoxycarbonyl group, a substituted or unsubstituted aromatic group, asubstituted or unsubstituted acyl group, a substituted or unsubstitutedalkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group,or a cycloalkyl group substituted by a substituted or unsubstitutedalkyl group,

provided that three or more of the groups represented by R^(1a)—X^(a),R^(1b)—X^(b), R^(1c)—X^(c) and R^(1d)—X^(d) are not hydrogen atoms atthe same time, and that when R^(1a), R^(1b), R^(1c) or R^(1d) is anunsubstituted alkyl group, the corresponding X^(a), X^(b), X^(c) orX^(d), respectively, is not a group represented by the formula: —C(═O)—,a prodrug of said compound or a pharmaceutically acceptable salt of saidcompound or prodrug.

-   -   [13] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [12],        wherein R^(1b) is a substituted or unsubstituted cycloalkyl        group, a substituted or unsubstituted cycloalkenyl group, a        substituted or unsubstituted saturated heterocyclic group, a        substituted or unsubstituted aromatic group, a substituted or        unsubstituted aroyl group, a substituted or unsubstituted        heteroaromatic acyl group, a substituted or unsubstituted        saturated heterocyclic carbonyl group, or a cycloalkyl group        substituted by a substituted or unsubstituted alkyl group.    -   [14] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [12],        wherein R^(1a) is a substituted or unsubstituted cycloalkyl        group, a substituted or unsubstituted cycloalkenyl group, a        substituted or unsubstituted saturated heterocyclic group, a        substituted or unsubstituted aromatic group, a substituted or        unsubstituted aroyl group, a substituted or unsubstituted        heteroaromatic acyl group, a substituted or unsubstituted        saturated heterocyclic carbonyl group, or a cycloalkyl group        substituted by a substituted or unsubstituted alkyl group.    -   [15] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [13],        wherein X^(b) is a group represented by the formula: —O—,        —N(R³)—, —NHC(═O)—, or —C(═O)NH—.    -   [16] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [14],        wherein X^(a) is a group represented by the formula: —O—,        —N(R³)—, —NHC(═O)—, or —C(═O)NH—.    -   [17] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [13],        wherein both of the groups represented by the formulas        R^(1c)—X^(c) and R^(1d)—X^(d) are hydrogen atoms.    -   [18] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [15],        wherein both of the groups represented by the formulas        R^(1c)—X^(c) and R^(1d)—X^(d) are hydrogen atoms.    -   [19] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [14],        wherein both of the groups represented by the formulas        R^(1c)—X^(c) and R^(1d)—X^(d) are hydrogen atoms.    -   [20] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [16],        wherein both of the groups represented by the formulas        R^(1c)—X^(c) and R^(1d)—X^(d) are hydrogen atoms.    -   [21] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [17],        wherein the groups represented by the formulas R^(1a) and X^(a)        are as follows:    -   (i) R^(1a) is a substituted or unsubstituted alkyl group and        X^(a) is a single bond, or    -   (ii) X^(a) is a group represented by the formula: —O—,        —C(═O)N(R³)—, —S(O)_(n)—, —S(O)₂N(R³)— or —C(═O)—.    -   [22] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [18],        wherein the groups represented by the formulas R^(1a) and X^(a)        are as follows:    -   (i) R^(1a) is a substituted or unsubstituted alkyl group and        X^(a) is a single bond, or    -   (ii) X^(a) is a group represented by the formula: —O—,        —C(═O)N(R³)—, —S(O)_(n)—, —S(O)₂N(R³)— or —C(═O)—.    -   [23] A compound, a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [22],        wherein the group represented by X^(a) is a group represented by        the formula: —O—.    -   [24] A pharmaceutical composition comprising a compound, a        prodrug thereof or a pharmaceutically acceptable salt of the        compound or prodrug according to any one of [10] to [23].    -   [25] A pharmaceutical composition for treatment of urinary        incontinence comprising a compound having inhibitory activity        against Rho kinase, as an active ingredient.    -   [26] A pharmaceutical composition for treatment of urinary        incontinence according to [25], wherein the compound having        inhibitory activity against Rho kinase is a compound represented        by the formula (1), a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [1].    -   [27] A pharmaceutical composition for treatment of urinary        incontinence according to [25], wherein the compound having        inhibitory activity against Rho kinase is a compound represented        by the formula (3), a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [10].    -   [28] A pharmaceutical composition for treatment of urinary        incontinence according to [25], wherein the compound having        inhibitory activity against Rho kinase is a compound represented        by the formula (2), a prodrug thereof or a pharmaceutically        acceptable salt of the compound or prodrug according to [2].

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the results of Test Example 2. The axis ofabscissa refers to acetylcholine concentration (plotted as the commonlogarithm of the reciprocal of the molar concentration) and the axis ofordinate refers to the rate of constriction of bladder (plotted as %).The open circles indicate an untreated group to which no drug has beenadded, and the closed circles indicate a group to which the compound ofExample 57 has been added in an amount of 100 μg/ml. Each value is shownas average value± standard error.

BEST MODE FOR CARRYING OUT THE INVENTION

The various groups in the present invention are explained below. Unlessotherwise specified, the following explanation applies to the case whereeach group is a portion of another group.

As the saturated or unsaturated heterocyclic 5-membered ring representedby the ring A, there are exemplified rings in which the three atomsother than the carbon atoms which the ring A shares with the benzenering in the compound of the formula (1) are as follows.

-   -   (a) 5-Membered rings having two nitrogen atoms and one carbon        atom.

Specific examples of the 5-membered ring fused with the benzene ring are1H-indazole, 1H-benzimidazole, 2,3-dihydro-1H-indazole and2,3-dihydro-1H-benzimidazole.

-   -   (b) 5-Membered rings having one nitrogen atom and two carbon        atoms.

Specific examples of the 5-membered ring fused with the benzene ring are1H-indole and 2,3-dihydro-1H-indole.

-   -   (c) 5-Membered rings having one nitrogen atom, one oxygen or        sulfur atom and one carbon atom.

Specific examples of the 5-membered ring fused with the benzene ring are1,3-benzothiazole, 1,3-benzoxazole, 2,3-dihydro-1,3-benzothiazole and2,3-dihydro-1,3-benzoxazole.

-   -   (d) 5-Membered rings having one oxygen or sulfur atom and two        carbon atoms.

Specific examples of the 5-membered ring fused with the benzene ring are1-benzofuran, 1-benzothiophene, 2,3-dihydro-1-benzofuran and2,3-dihydro-1-benzothiophene.

Preferable examples of the saturated or unsaturated heterocyclic5-membered ring represented by the ring A are rings represented by thefollowing structural formula when fused with the benzene ring in thecompound of the formula (1):

wherein Y¹, Y² and Y³ are as defined above.

As the alkylene group, there are exemplified linear or branched alkylenegroups of 8 or less carbon atoms, such as methylene, ethylene,trimethylene, tetramethylene, etc. Preferable examples thereof arealkylene groups of 1 to 4 carbon atoms.

The alkyl group includes lower alkyl groups. Specific examples thereofare linear or branched alkyl groups of 8 or less carbon atoms, such asmethyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl,1,1-dimethylethyl, pentyl, hexyl, heptyl, octyl, etc.

The cycloalkyl group includes lower cycloalkyl groups. Specific examplesthereof are 3- to 8-membered cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; groups having acrosslinkage, such as adamantyl, bicyclo[2.2.2]octane,bicyclo[3.3.3]undecane, etc.; and fused-ring cycloalkyl groups such asdecahydronaphthalene, octahydro-1H-indene, etc.

The cycloalkenyl group includes lower cycloalkenyl groups. Specificexamples thereof are 3- to 8-membered cycloalkenyl groups having adouble bond, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl,1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, etc.; and cycloalkenylgroup having a crosslinkage, such as bicyclo[2.2.2]oct-2-ene,bicyclo[3.3.3]undec-2-ene, etc.

As the aromatic group, aryl group and heteroaryl group are exemplified.

As the aryl group, there are exemplified aryl groups of 10 or lesscarbon atoms, such as phenyl group, naphthyl group, etc. The aryl groupalso includes those having an unsaturated heterocyclic ring fusedtherewith, such as 2,3-dihydro-1-benzofuran-5-yl, etc.

As the heteroaryl group, there are exemplified 5- or 6-memberedmonocyclic groups containing one or two nitrogen atoms, 5- or 6-memberedmonocyclic groups containing one or two nitrogen atoms and one oxygenatom or one sulfur atom, 5-membered monocyclic groups containing oneoxygen atom or one sulfur atom, and bicyclic groups formed by the fusionof a 6-membered ring and a 5- or 6-membered ring and containing 1 to 4nitrogen atoms. Specific examples thereof are 2-pyridyl, 3-pyridyl,4-pyridyl, 2-thienyl, 3-thienyl, 3-oxadiazolyl, 2-imidazolyl,2-thiazolyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-furyl, 3-furyl,3-pyrrolyl, 2-quinolyl, 8-quinolyl, 2-quinazolyl, 8-purinyl, etc.

As the halogen atom, iodine, fluorine, chlorine and bromine atoms areexemplified.

As the arylalkyl group, alkyl groups substituted by any of theabove-exemplified aryl groups are exemplified.

As the cycloalkylalkyl group, alkyl groups substituted by any of theabove-exemplified cycloalkyl groups are exemplified.

As the saturated heterocyclic alkyl group, alkyl groups substituted byany of the saturated heterocyclic groups exemplified below areexemplified.

As the saturated heterocyclic group, there are exemplified 5- to8-membered cyclic groups having a nitrogen atom, such as 1-piperidinyl,1-pyrrolidinyl, etc.; 6- to 8-membered cyclic groups having two nitrogenatoms, such as 1-piperazinyl, etc.; 6- to 8-membered cyclic groupshaving a nitrogen atom and an oxygen atom, such as morpholino, etc.; and5- to 8-membered cyclic groups having a group represented by theformula: —O—, —S—, —S(O)— or —S(O)₂—, such as tetrahydro-2H-pyran-4-yl,tetrahydro-2H-thiopyran-4-yl, 1-oxytetrahydro-2H-thiopyran-4-yl,1,1-dioxytetrahydro-2H-thiopyran-4-yl, etc.; groups having acrosslinkage, such as quinuclidinyl, 1-azabicyclo[2.2.1]heptyl,1-azabicyclo[3.2.1]octyl, etc.; and fused saturated heterocyclic groupssuch as decahydroquinoline, octahydro-1H-indole, etc. The saturatedheterocyclic group also includes those having an aromatic ring fusedtherewith, such as 1H-isoindole 1,3(2H)-dion-2-yl, etc.

As the substituent of each of the saturated heterocyclic group and thesaturated heterocyclic carbonyl group, there are exemplifiedsubstituents on a carbon atom, such as substituted or unsubstitutedalkyl groups, hydroxyl group, oxo group, carboxyl group, halogen atoms,alkoxycarbonyl groups, etc.; and substituents on a nitrogen atom, suchas substituted or unsubstituted alkyl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted cycloalkyl groups, substituted orunsubstituted cycloalkylalkyl groups, alkyl-substituted or unsubstitutedsaturated heterocyclic groups, saturated heterocyclic groups which maybe substituted by an aryl group, arylalkyl group, alkoxycarbonyl group,alkanoyl group or lower alkyl group, and groups represented by theformula: —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or —S(O)_(m)R¹¹ (R⁹, R¹⁰, R¹¹ and mare as defined above).

As the acyl group, there are exemplified formyl group; alkanoyl groupsof 2 to 6 carbon atoms, such as acetyl, propanoyl, etc.;cycloalkanecarbonyl groups of 4 to 7 carbon atoms, such ascyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, etc.; cycloalkenecarbonyl groups of 3 to 6 carbonatoms, such as cyclopentenecarbonyl, cyclohexenecarbonyl, etc.; aroylgroups of 6 to 10 carbon atoms, such as benzoyl, toluoyl, naphthoyl,etc.; saturated heterocyclic carbonyl groups having a 5- or 6-memberedsaturated heterocyclic ring containing one or two heteroatoms selectedfrom nitrogen atom, oxygen atom and sulfur atom, such as2-piperidinecarbonyl, 3-morpholinecarbonyl, etc.; and heteroaromaticacyl groups having a 5- or 6-membered heteroaromatic ring containing oneor two heteroatoms selected from nitrogen atom, oxygen atom and sulfuratom, or heteroaromatic acyl groups having a heteroaromatic ring havinga benzene ring fused therewith, such as 2-furoyl, 3-furoyl, 2-thenoyl,3-thenoyl, nicotinoyl, isonicotinoyl, 5-indazolylcarbonyl, etc.

Each of the alkylene group, the alkyl group, the cycloalkyl group, thealkanoyl group, the cycloalkanecarbonyl group, the cycloalkenecarbonylgroup, and the alkyl portion of the arylalkyl group may have one or moresubstituents which may be the same or different. As the substituents,there are exemplified halogen atoms, cyano group, aromatic groups,alkenyl groups, phenoxy group, benzyloxy group, trifluoromethyl group,hydroxyl group, lower alkoxy groups, saturated heterocyclic ring-oxygroups, lower alkoxy-lower alkoxy groups, lower alkanoyloxy groups,amino group, nitro group, carbamoyl group, lower alkylaminocarbonylgroups, di-lower-alkylaminocarbonyl group, lower alkoxycarbonylaminogroups, benzyloxycarbonylamino group, lower alkylsulfonylamino-loweralkyl groups, carboxyl group, lower alkoxycarbonyl groups, loweralkylthio groups, lower alkylsulfinyl groups, lower alkylsulfonylgroups, lower alkylsulfonamide groups, tri-lower-alkylsilyl groups,phthalimide group, aryl groups, heteroaryl groups, cycloalkyl groups,cycloalkenyl groups, alkyl groups, alkynyl groups, lower alkylaminoalkylgroups, di-lower-alkylaminoalkyl groups, saturated heterocyclic groups,saturated heterocyclic ring-oxy groups, oxo group, saturatedheterocyclic carbonylamino groups, cycloalkanecarbonylamino groups, andamino groups substituted by one or more groups which may be the same ordifferent and are represented by the formula: R¹²—R¹³— wherein R¹² is alower alkoxycarbonyl group, a lower alkyl group, an aromatic group, acycloalkyl group, a saturated heterocyclic group, a benzoyl group or alower alkanoyl group (said lower alkoxycarbonyl group, lower alkylgroup, aromatic group, cycloalkyl group, saturated heterocyclic group,benzoyl group or lower alkanoyl group may be substituted by one or moresubstituents which may be the same or different and are selected fromhydroxyl group, amino group, mono-lower-alkylamino groups,di-lower-alkylamino groups, halogen atoms, lower alkoxy groups,benzyloxy group, benzyl group, methylenedioxy group and trifluoromethylgroup; and R¹³ is a single bond or a lower alkylene group).

Each of the aromatic group, the aroyl group, the phenyl group, theheteroaromatic acyl group and the aryl portion of the arylalkyl groupmay have one or more substituents which may be the same or different. Asthe substituents, there are exemplified halogen atoms, cyano group,trifluoromethyl group, trifluoromethoxy group, nitro group, hydroxylgroup, methylenedioxy group, lower alkyl groups which may besubstituted, lower alkoxy groups, benzyloxy group, lower alkanoyloxygroups, amino group, mono-lower-alkylamino groups, di-lower-alkylaminogroups, monocycloalkylamino groups, dicycloalkylamino groups, carboxylgroup, lower alkoxycarbonyl groups, lower alkylthio groups, loweralkylsulfinyl groups, lower alkylsulfonyl groups, lower alkanoylaminogroups, lower alkylsulfonamide groups, aminosulfonyl group, andcarbamoyl groups substituted by one or more lower alkyl groups orcycloalkyl groups, which may be substituted and may be the same ordifferent. There are also exemplified saturated heterocyclic carbonylgroups that may be substituted by a benzyl group or a hydroxyl group.

As the heteroatom of the substituted or unsubstituted saturated 5- to8-membered cyclic amino group which may contain another heteroatom inthe ring and which R⁹ and R¹⁰ form when taken together with the nitrogenatom to which they are bonded, there are exemplified oxygen atom, sulfuratom and nitrogen atom. Specific examples of such cyclic amino group arepyrrolidine and piperidine. As the substituent, there are exemplifiedsubstituted or unsubstituted alkyl groups and groups represented by theformula: —OR⁸¹. Here, as R⁸¹, there are exemplified hydrogen atom,substituted or unsubstituted alkyl groups, substituted or unsubstitutedcycloalkyl groups, substituted or unsubstituted cycloalkenyl groups,substituted or unsubstituted saturated heterocyclic groups, substitutedor unsubstituted alkoxycarbonyl groups, substituted or unsubstitutedaromatic groups, substituted or unsubstituted acyl groups, andsubstituted or unsubstituted arylalkyl groups.

The term “lower” means that the alkyl portion of the substituentconcerned is a lower alkyl group. As such a lower alkyl group, there areexemplified groups of 4 or less carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

The term “alkoxy group” means a group having the above-mentioned alkylgroup bonded to one of the direct links of an oxygen atom.

The term “alkoxycarbonyl group” means a group having the above-mentionedalkoxy group bonded to one of the direct links of a carbonyl group.

The term “alkanoyl group” means a group having the above-mentioned alkylgroup bonded to one of the direct links of a carbonyl group.

The term “cycloalkylalkyl group” means a group having on its alkyl groupone or more cycloalkyl groups which may be the same or different, assubstituent(s).

The term “haloalkyl group” means a group having on its alkyl group oneor more halogen atoms which may be the same or different, assubstituent(s).

The term “hydroxyalkyl group” means a group having on its alkyl groupone or more hydroxyl groups as substituent(s).

The passage “when X is a group represented by the formula: —N(R³)C(═O)—,—C(═O)N(R³)—, —N(R³)S(O)₂— or —S(O)₂N(R³)— in the compound representedby the formula (1)” means that R¹ is bonded to the left side of X and abenzene ring fused with the ring A is bonded to the right side of X.Also in other definitions, when different compounds are formed dependingon the directions of bonding of divalent groups, each structural formulameans that the divalent groups are bonded in the directions shown in thestructural formula, unless otherwise specified.

As the compounds according to the above items [13] to [16] which haveinhibitory effect on Rho kinase in the invention of the pharmaceuticalcomposition for treatment of urinary incontinence, there are exemplifiedthe compounds disclosed in International Patent Laid-Open No.WO98/06433, in particular,(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane; thecompounds disclosed in International Patent Laid-Open No. WO99/64011;the compounds disclosed in International Patent Laid-Open No.WO00/57914; and the compounds represented by the above general formula(1), prodrugs thereof, and pharmaceutically acceptable salts of thecompounds or prodrugs.

The compound represented by the formula (1) may be synthesized from awell-known compound by a combination of well-known synthesis processes.It may be synthesized, for example, by any of the following processes.

-   -   (A) A compound of the formula (1) in which X is a group        represented by the formula: —NH— may be synthesized, for        example, as follows.

wherein each of R^(1a) and R^(1b) is a hydrogen atom or a substituted orunsubstituted alkyl group, or R^(1a) and R^(1b), when taken togetherwith the carbon atoms to which they are bonded, form a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, or a substituted or unsubstituted saturatedheterocyclic group; and the ring A and R² are as defined above.

The compound of the formula (1) in which X is a group represented by theformula: —NH— may be produced, for example, by subjecting a compoundrepresented by the formula (2) to reductive amination reaction with acompound represented by the formula: R^(1a)C(═O)R^(1b) in an inertsolvent in the presence of a reducing agent at room temperature or withheating.

As the reducing agent, there may be used reducing agents includingcomposite hydrogen compounds such as sodium triacetoxyborohydride,lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,etc.; and diborane. There may also be employed reduction with sodium,sodium amalgam or zinc-acid, and electrical reduction using lead orplatinum as a cathode. As the solvent, there are exemplified alcoholsolvents such as methanol, ethanol, etc.; ether solvents such astetrahydrofuran, 1,4-dioxane, etc.; halogenated hydrocarbon solventssuch as dichloromethane, chloroform, 1,2-dichloroethane, etc.; and mixedsolvents thereof.

-   -   (B) A compound of the formula (1) in which X is a group        represented by the formula: —CONH— may be synthesized, for        example, as follows.

wherein the ring A, R¹ and R² are as defined above.

The compound of the formula (1) in which X is a group represented by theformula: —CONH—, i.e., a compound of the formula (3) may be produced byreacting a compound represented by the formula (2) with a compoundrepresented by the formula: R¹COOH in an inert solvent in the presenceof a condensing agent at room temperature or with heating, or byreacting a compound represented by the formula (2) with a correspondingacid halide or acid anhydride in an inert solvent in the presence of abase at room temperature or with heating.

As the condensing agent, there are used condensing agents such asdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC),benzotriazol-1-yl-tris(dimethylamino)phosphonium•hexafluorophosphate(BOP), diphenylphosphonyldiamide (DPPA), N,N-carbonyldiimidazole (Angew.Chem. Int. Ed. Engl., Vol. 1, 351(1962)), etc. If necessary, there maybe added additives such as N-hydroxysuccinimide (HOSu),1-hydroxybenzotriazole (HOBt),3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc. As thesolvent, there are exemplified aromatic hydrocarbon solvents such asbenzene, toluene, xylene, etc.; ether solvents such as tetrahydrofuran,1,4-dioxane, etc.; halogenated hydrocarbon solvents such asdichloromethane, chloroform, 1,2-dichloroethane, etc.; amide solventssuch as dimethylformamide, dimethylacetamide, etc.; basic solvents suchas pyridine, etc.; and mixed solvents thereof. As the base, there areexemplified inorganic bases such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, etc.; and organic bases such as triethylamine,pyridine, etc. As the acid halide, acid chlorides and acid bromides areexemplified.

-   -   (C) A compound of the formula (1) in which X is a group        represented by the formula: —CH₂NH— may be synthesized, for        example, as follows.

wherein the ring A, R¹ and R² are as defined above.

The compound of the formula (1) in which X is a group represented by theformula: —CH₂NH— may be produced, for example, by reducing an amidederivative represented by the formula (3) with a reducing agent such aslithium aluminum hydride, diborane or the like in an inert solvent suchas tetrahydrofuran, 1,4-dioxane or the like at room temperature or withheating.

-   -   (D) A compound of the formula (1) in which X is a group (an        oxygen atom) represented by the formula: —O— may be synthesized,        for example, as follows.

wherein the ring A, R¹ and R² are as defined above.

The compound of the formula (1) in which X is a group represented by theformula: —O— may be produced, for example, by reacting a compoundrepresented by the formula (4) with a compound represented by theformula: R¹OH in an inert solvent in the presence of, for example,diethyl azodicarboxylate and triphenylphosphine at room temperature orwith heating.

-   -   (E) A compound of the formula (1) in which X is a group        represented by the formula: —NHCO— may be synthesized, for        example, as follows.

wherein the ring A, R¹ and R² are as defined above.

The compound of the formula (1) in which X is a group represented by theformula: —NHCO— may be produced, for example, by reacting a compound ofthe formula (5) with a compound represented by the formula: R¹NH in aninert solvent in the presence of a condensing agent at room temperatureor with heating.

As the condensing agent, there are used condensing agents such asdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC),benzotriazol-1-yl-tris(dimethylamino)phosphonium•hexafluorophosphate(BOP), diphenylphosphonyldiamide (DPPA), N,N-carbonyldiimidazole (Angew.Chem. Int. Ed. Engl., Vol. 1, 351(1962)), etc. If necessary, there maybe used additives such as N-hydroxysuccinimide (HOSu),1-hydroxybenzotriazole (HOBt),3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc.

As the solvent, there are exemplified aromatic hydrocarbon solvents suchas benzene, toluene, xylene, etc.; ether solvents such astetrahydrofuran, 1,4-dioxane, etc.; halogenated hydrocarbon solventssuch as dichloromethane, chloroform, 1,2-dichloroethane, etc.; amidesolvents such as dimethylformamide, dimethylacetamide, etc.; basicsolvents such as pyridine, etc.; and mixed solvents thereof.

-   -   (F) A compound of the formula (1) in which X is a group        represented by the formula: —N(R³)— may be synthesized, for        example, as follows.

wherein the ring A, R¹, R² and R³ are as defined above.

The compound of the formula (1) in which X is a group represented by theformula: —N(R³)— may be produced, for example, by reacting a compoundrepresented by the formula (6) with a compound represented by theformula: R¹R³NH in an inert solvent in the presence of, a palladiumcatalyst at room temperature or with heating.

As the palladium catalyst, there may be used catalysts such asbis(tri-O-tolylphosphine)-palladium(II) dichloride, palladium acetate,etc. As the solvent, toluene, 1,4-dioxane and dimethylacetamide areexemplified.

-   -   (G) The compound of the formula (2) used as a staring material        in the above production processes may be a per se well-known        compound, or produced by a well-known process or a combination        of well-known processes (as references, there are        exemplified A. R. Katritzky and C. W. Rees, COMPREHENSIVE        HETEROCYCLIC CHEMISTRY The structure, Reactions, Synthesis and        Uses of Heterocyclic Compounds Volume 5, PERGAMON PRESS;        Heterocycles, 1995, 41(3), 487–496; J. Chem. Research, Synop,        1990, (11), 350–351; J. Chem. Research, Miniprint, 1990, (11),        2601–2615; Synth. Commun., 1996, 26(13), 2443–2447; and Synth.        Commun., 1999, 29(14), 2435–2445).

The compound of the formula (4) used as a staring material in the aboveproduction process may be a per se well-known compound, or produced by awell-known process or a combination of well-known processes (asreferences, there are exemplified Helv. Chim. Acta, 1976, 59, 2618–2620;J. Chem. Soc., 1955, 2412–2418; and J. Chem. Soc., 1960, 2735–2738).

The compound of the formula (5) used as a staring material in the aboveproduction process may be a per se well-known compound, or produced by awell-known process or a combination of well-known processes (asreferences, there are exemplified J. Med. Chem., 2000, 43, 41–58; andHelv. Chim. Acta, 1976, 59, 2618–2620).

The compound of the formula (6) used as a staring material in the aboveproduction process may be a per se well-known compound, or produced by awell-known process or a combination of well-known processes (asreferences, there are exemplified Tetrahedron, 1994, 50(11), 3529–3536;and International Patent Laid-Open No. WO2000-063207).

In each of the above production processes, when the starting compound ineach reaction has a reactive group such as a hydroxyl group, amino groupor carboxylic acid group, such a group other than a site desired to bereacted is previously protected with a suitable protective group ifnecessary, and the protective group is removed after carrying out eachreaction or several reactions, whereby a desired compound may beobtained. As the protective group for protecting the hydroxyl group,amino group or carboxyl group, an ordinary protective group used in thefield of organic synthetic chemistry may be used. The introduction andremoval of such a protective group may be carried out according to ausual method (for example, the method described in T. W. Green and P. G.M. Wuts, Protective Groups in Organic Synthesis, Second Edition, JohnWiley & Sons, Inc. (1991)).

For example, as a protective group for the hydroxyl group, methoxymethylgroup and tetrahydropyranyl group are exemplified. As a protective groupfor the amino group, tert-butoxycarbonyl group is exemplified. Theprotective group for the hydroxyl group may be removed by reaction in asolvent such as aqueous methanol, aqueous ethanol or aqueoustetrahydrofuran in the presence of an acid such as hydrochloric acid,sulfuric acid or acetic acid. The protective group for the amino groupmay be removed by reaction in a solvent such as aqueous tetrahydrofuran,methylene chloride, chloroform or aqueous methanol in the presence of anacid such as hydrochloric acid or trifluoroacetic acid.

As a protective form for protecting the carboxyl group, tert-butylesters, orthoestes and acid amides are exemplified. Such a protectivegroup is removed as follows. In the case of the tert-butyl ester, theremoval is carried out, for example, by reaction in an aqueous solventin the presence of hydrochloric acid. In the case of the orthoester, theremoval is carried out by treatment with an acid and then an alkali suchas sodium hydroxide in a solvent such as aqueous methanol, aqueoustetrahydrofuran or aqueous 1,2-dimethoxyethane. In the case of the acidamide, the removal is carried out by reaction in a solvent such aswater, aqueous methanol or aqueous tetrahydrofuran in the presence of anacid such as hydrochloric acid or sulfuric acid.

The compound represented by the formula (1) includes those having anoptical center of asymmetry. Therefore, the compound having an opticalcenter of asymmetry may be obtained as a racemate, or it may be obtainedas an optically active substance when an optically active startingmaterial is used. If necessary, the racemic modification obtained may bephysically or chemically resolved into optical antipodes by a well-knownmethod. Preferably, diastereomers are formed from the racemicmodification by a reaction using a reagent for optical resolution. Thediastereomers different in form may be resolved by a well-known methodsuch as fractional crystallization.

As the “prodrug”, there are exemplified those which are easilyhydrolyzed in a living body to regenerate the compound of the formula(1). For example, when the compound of the formula (1) has a carboxylgroup, examples of the prodrug are compounds obtained by converting thecarboxyl group to an alkoxycarbonyl group, an alkylthiocarbonyl group oran alkylaminocarbonyl group. For example, when the compound of theformula (1) has an amino group, examples of the prodrug are compoundsobtained by converting the amino group to an alkanoylamino group bysubstitution by the alkanoyl group, compounds obtained by converting theamino group to an alkoxycarbonylamino group by substitution by thealkoxycarbonyl group, and compounds obtained by converting the aminogroup to an acyloxymethylamino group or hydroxylamine. For example, whenthe compound of the formula (1) has a hydroxyl group, examples of theprodrug are compounds obtained by converting the hydroxyl group to anacyloxy group by substitution by the above-exemplified acyl group, andcompounds obtained by converting the hydroxyl group to a phosphoricester or an acyloxymethyloxy group. Examples of the alkyl portion of thegroup used for such conversion to the prodrug are the above-exemplifiedalkyl groups. The alkyl groups may be substituted by, for example, analkoxy group of 1 to 6 carbon atoms. Preferable examples of the alkylportion are as follows. For example, in the case of compounds obtainedby converting the carboxyl group to an alkoxycarbonyl group, thealkoxycarbonyl group includes lower (number of carbon atoms: forexample, 1 to 6) alkoxycarbonyls such as methoxycarbonyl,ethoxycarbonyl, etc.; and lower (number of carbon atoms: for example, 1to 6) alkoxycarbonyls substituted by an alkoxy group, such asmethoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl,2-methoxyethoxymethoxycarbonyl, pivaloyloxymethoxy-carbonyl, etc.

If necessary, the compound represented by the formula (1) or the prodrugthereof may be converted to a pharmaceutically acceptable salt. As sucha salt, there are exemplified salts with mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,etc.; salts with organic carboxylic acids such as formic acid, aceticacid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid,tartaric acid, aspartic acid, glutamic acid, etc.; salts with sulfonicacids such as methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, hydroxybenzenesulfonic acid,dihydroxybenzenesulfonic acid, etc.; and alkali metal salts such assodium salt, potassium salt, etc.; alkaline earth metal salts such ascalcium salt, magnesium salt, etc.; ammonium salt; triethylamine salt,pyridine salt, picoline salt, ethanolamine salt, dicyclohexylamine salt,and salt with N,N′-dibenzylethylenediamine.

Each of the compounds represented by the formula (1), the prodrugsthereof and the pharmaceutically acceptable salts of the compounds orprodrugs may be in the form of an anhydride, hydrate or solvate.

When used as a pharmaceutical composition, the compound of the presentinvention may be orally or parenterally administered. That is, thecompound may be orally administered in a usual dosage form such aspowder, granules, tablets, capsules, syrup, suspension or the like, orthe compound may be parenterally administered, for example, by injectionof a solution, emulsion or suspension prepared from the compound. Thecompound may be administered rectally in the form of a suppository. Theabove-exemplified suitable dosage forms may be prepared by blending thecompound of the present invention with, for example, a carrier,excipient, binder, stabilizer and diluent which are acceptable andordinary. When the compound is used in the form of an injection, theinjection may be incorporated with, for example, a buffer, solubilizerand tonicity agent which are acceptable. Although the dose and thenumber of administrations are varied depending on, for example, adisease to be cured, the condition of the disease, age, body weight andadministration route, the compound may be administered to an adult in adose of usually 0.1 to 2,000 mg, preferably 1 to 200 mg per day in oneportion or several portions (for example, 2 to 4 portions).

Examples of the compound of the present invention are given below. Inthe following general formulas, Me denotes a methyl group, Et an ethylgroup, Pr a n-propyl group, Bu a n-butyl group, and Ms a methanesulfonylgroup.

-   [1] Compounds represented by the following formula

wherein R is any of the groups listed in the following Table 1, Table 2or Table 3.

TABLE 1 R 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

TABLE 2 R 40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

TABLE 3 R 79

80

81

82

83

84

-   [2] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [3] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [4] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [5] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [6] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [7] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [8] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [9] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [10] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [11] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [12] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [13] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [14] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [15] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [16] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [17] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [18] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [19] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [20] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [21] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [22] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [23] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [24] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [25] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [26] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [27] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [28] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [29] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [30] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [31] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [32] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [33] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [34] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [35] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [36] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [37] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [38] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [39] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [40] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [41] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [42] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [43] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [44] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [45] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [46] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [47] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [48] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [49] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [50] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [51] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [52] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [53] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [54] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [55] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [56] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [57] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [58] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [59] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [60] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [61] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [62] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [63] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [64] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [65] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [66] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [67] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [68] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [69] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [70] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [71] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [72] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [73] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [74] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [75] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [76] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [77] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

-   [78] Compounds represented by the following formula:

wherein R is any of the groups listed in the above Table 1, Table 2 orTable 3.

The present invention is more concretely illustrated below withreference examples, working examples and test examples, which should notbe construed as limiting the scope of the invention. The nomenclature ofcompounds shown in the reference examples and working examples mentionedbelow is not always based on IUPAC.

REFERENCE EXAMPLE 1 Synthesis of 1H-indazole-5-carboxylic acid

Water (20 ml) and concentrated sulfuric acid (20 ml) were added to asolution of 1H-indazole-5-carbonitrile (3.00 g, 20.1 mmol) in aceticacid (20 ml) at room temperature, and the resulting mixture was heatedat 100° C. for 3 hours. Then, the reaction solution was poured onto iceand the solid precipitated was collected by filtration and dried underreduced pressure to obtain 1H-indazole-5-carboxylic acid (2.88 g, 88%).

¹H-NMR (DMSO-d₆) δ; 7.58 (1H, d, J=8.6 Hz), 7.90 (1H, dd, J=8.6, 1.4Hz), 8.23 (1H, s), 8.44 (1H, d, J=0.7 Hz), 12.75 (1H, brs), 13.59 (1H,brs).

REFERENCE EXAMPLE 2 Synthesis of 1H-indazol-5-ylmethanol (a) Synthesisof methyl 1H-indazole-5-carboxylate

A solution of sodium nitrite (836 mg, 59.1 mmol) in water (2 ml) wasadded to a solution of methyl 4-amino-3-methylbenzoate (2.00 g, 12.1mmol) in acetic acid (80 ml) at room temperature and stirred at roomtemperature for 5 hours. The reaction solution was concentrated and theresulting residue was diluted with chloroform and washed with a 5%aqueous sodium hydrogencarbonate solution and then a saturated aqueoussodium chloride solution. The organic layer was dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent, and the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate=3/1) to obtain methyl1H-indazole-5-carboxylate (645 mg, 30%).

¹H-NMR (DMSO-d₆) δ; 3.86 (3H, s), 7.61 (1H, d, J=8.8 Hz), 7.91 (1H, d,J=8.8 Hz), 8.25 (1H, s), 8.48 (1H, brs), 13.41 (1H, brs).

(b) Synthesis of 1H-indazole-5-ylmethanol

A solution of methyl 1H-indazole-5-carboxylate (825 mg, 4.68 mmol) intetrahydrofuran (20 ml) was added to a solution of lithium aluminumhydride (580 mg, 14.1 mmol) in tetrahydrofuran (16 ml) at 0° C. andstirred at 0° C. for 1 hour. A mixture of tetrahydrofuran (10 ml) andwater (10 ml) was added to the reaction solution and the resultingmixture was filtered. The filtrate was concentrated and the resultingresidue was diluted with chloroform and washed with a 1N-aqueous sodiumhydroxide solution and then a saturated aqueous sodium chloridesolution. The organic layer was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent, whereby1H-indazole-5-ylmethanol (260 mg, 38%) was obtained.

¹H-NMR (DMSO-d₆) δ; 4.55 (1H, d, J=5.5 Hz), 5.14 (1H, t, J=5.5 Hz), 7.30(1H, dd, J=1.1, 8.4 Hz), 7.47 (1H, d, J=8.4 Hz), 7.46 (1H, s), 8.01 (1H,s), 12.97 (1H, brs).

REFERENCE EXAMPLE 3 Synthesis of 5-(bromomethyl)-1H-indazolehydrobromide

1H-indazole-5-ylmethanol (100 mg, 0.675 mmol) was added to a 48% aqueoushydrogen bromide solution (2.0 ml) at room temperature and stirred atroom temperature for 15 hours and then at 50° C. for 5 hours.Subsequently, the reaction solution was filtered and the resulting solidwas dried under reduced pressure to obtain 5-(bromomethyl)-1H-indazolehydrobromide (156 mg, 79%).

¹H-NMR (DMSO-d₆) δ; 4.86 (2H, s), 7.42 (1H, dd, J=8.6, 1.7 Hz), 7.51(1H, d, J=8.6 Hz), 7.84 (1H, s), 8.07 (1H, d, J=1.7 Hz).

REFERENCE EXAMPLE 4 Synthesis of 1H-indazol-5-ol (a) Synthesis of5-methoxy-1H-indazole

A solution of sodium nitrite (3.38 g, 49.0 mmol) in water (8.1 ml) wasadded to a solution of 4-methoxy-2-methylaniline (6.69 g, 48.8 mmol) inacetic acid (350 ml) in an ice-water bath while maintaining thetemperature at 25° C. or lower, and stirred overnight at roomtemperature. Then, the reaction solution was poured into water andextracted with chloroform. The organic layer was washed with a saturatedaqueous sodium chloride solution, dried over anhydrous magnesium sulfateand then distilled under reduced pressure to remove the solvent, and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol=9/1) to obtain 5-methoxy-1H-indazole (1.30g, 18%).

¹H-NMR (DMSO-d₆) δ; 3.76 (3H, s), 6.98 (1H, dd, J=8.8, 1.8 Hz), 7.15(1H, d, J=1.8 Hz), 7.42 (1H, d, J=8.8 Hz), 7.93 (1H, s), 12.89 (1H,brs).

(b) Synthesis of 1H-indazol-5-ol

A methylene chloride solution of boron tribromide (18.5 ml, 18.5 mmol)was added to a solution of 5-methoxy-1H-indazole (1.24 g, 8.40 mmol) inmethylene chloride (84 ml) at 0° C. and stirred at room temperature for10 hours. Then, water was poured into the reaction solution in anice-water bath, followed by extraction with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium hydrogencarbonatesolution and then a saturated aqueous sodium chloride solution, driedover anhydrous magnesium sulfate, and distilled under reduced pressureto remove the solvent, and the resulting residue was purified by asilica gel column chromatography (eluent: chloroform/methanol=96/4) toobtain 1H-indazol-5-ol (877 mg, 71%).

¹H-NMR (DMSO-d₆) δ; 6.88 (1H, dd, J=8.8, 2.2 Hz), 6.96 (1H, d, J=2.2Hz), 7.34 (1H, d, J=8.8 Hz), 7.84 (1H, s).

REFERENCE EXAMPLE 5 Synthesis of5-bromo-1-tetrahydro-2H-pyran-2-yl-1H-indazole

3,4-dihydro-2H-pyran (0.84 ml, 9.21 mmol) and pyridiniump-toluenesulfonate (202 mg, 0.804 mmol) were added to a solution of5-bromo-1H-indazole (790 mg, 4.01 mmol) in methylene chloride (15 ml) atroom temperature, and the resulting mixture was refluxed for 6 hours.Then, the reaction solution was poured into a saturated aqueous sodiumhydrogencarbonate solution and extracted with chloroform. The organiclayer was washed with a saturated aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure and the resulting residue was purified by asilica gel column chromatography (eluent: hexane/ethyl acetate=93/7) toobtain 5-bromo-1-tetrahydro-2H-pyran-2-yl-1H-indazole (1.06 g, 94%).

¹H-NMR (DMSO-d₆) δ; 1.64–1.85 (3H, m), 2.06–2.17 (2H, m), 2.48–2.59 (1H,m), 3.70–3.78 (1H, m), 3.99–4.03 (1H, m), 5.66 (1H, dd, J=8.9, 2.9 Hz),7.46 (1H, dd, J=9.0, 1.7 Hz), 7.48–7.52 (1H, m), 7.87 (1H, dd, J=1.7,0.9 Hz), 7.96 (1H, d, J=0.6 Hz), 7.84 (1H, s).

EXAMPLE 1 Synthesis of N-(1-benzyl-4-piperidinyl)-1H-indazol-5-aminedihydrochloride monohydrate (a) Synthesis ofN-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine

To a solution of 1-benzyl-4-piperidone (7.11 g, 37.6 mmol) in1,2-dichloroethane (125 ml) were added 5-aminoindazole (5.00 g, 37.6mmol), sodium triacetoxyborohydride (11.5 g, 52.6 mmol) and acetic acid(2.15 ml, 37.6 mmol) at room temperature, and stirred overnight at roomtemperature. Then, the reaction solution was poured into a 1N-aqueoussodium hydroxide solution and extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure and the resulting residue was purified by asilica gel column chromatography (eluent: ethyl acetate/methanol=100/1)to obtain N-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine (8.56 g, 74%).

Melting point: 174–176° C.

(b) Synthesis of N-(1-benzyl-4-piperidinyl)-1H-indazol-5-aminedihydrochloride monohydrate

To a solution of N-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine (3.06 g,10.0 mmol) in tetrahydrofuran (31 ml) was added a 1N-hydrochloricacid/ether solution (25 ml) at room temperature, and stirred at roomtemperature for 30 minutes. The solid precipitated was collected byfiltration and recrystallized from methanol to obtainN-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine dihydrochloridemonohydrate (2.86 g, 72%).

Melting point: 257–259° C. (decomp.).

The following compounds of Example 2 to Example 14 were synthesized bycarrying out reaction according to the method described in Example 1.

EXAMPLE 2 N-[1-(2-phenylethyl)-4-piperidinyl)]-1H-indazol-5-aminedihydrochloride

Melting point: 285–287° C. (decomp.)

EXAMPLE 3 N-(1-isopropyl-4-piperidinyl)-1H-indazol-5-amine

Melting point: 140–141° C.

EXAMPLE 4 N-(1-benzoyl-4-piperidinyl)-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.32 (2H, m), 1.98 (2H, m), 3.12 (2H, m), 3.52 (2H,m), 4.32 (1H, m), 5.22 (1H, d, J=8.3 Hz), 6.72 (1H, m), 6.82 (1H, dd,J=8.8, 2.0 Hz), 7.26 (1H, J=8.8 Hz), 7.35–7.45 (5H, m), 7.73 (1H, d,brs), 12.58 (1H, brs).

EXAMPLE 5 N-{[4-(dimethylamino)-1-naphthy]methyl}-1H-indazol-5-amine

Melting point: 143–144° C.

EXAMPLE 6 N-[(2-methoxy-1-naphthyl)methyl]-1H-indazol-5-amine

Melting point: 183–185° C.

EXAMPLE 7 1-[(1H-indazol-5-ylamino)methyl}-2-naphtohol

Melting point: 142–144° C.

EXAMPLE 8 N-(1H-indol-3-ylmethyl)-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 4.13 (2H, s), 4.56 (2H, s), 6.80–6.86 (2H, m),6.97–7.02 (1H, m), 7.08 (1H, d, J=2.2 Hz), 7.12 (1H, d, J=9.0 Hz), 7.28(1H, d, J=8.1 Hz), 7.49 (1H, d, J=7.7 Hz), 7.84 (1H, brs), 10.72 (1H,s), 12.53 (1H, brs).

EXAMPLE 9 N-(4-quinolinylmethyl)-1H-indazol-5-amine

Melting point: 244–246° C. (decomp.)

EXAMPLE 10 N-(1,2,3,4-tetrahydro-2-naphthalenyl)-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.53–1.56 (1H, m), 2.12 (1H, m), 2.62–2.70 (1H, m),2.85–2.89 (2H, m), 3.08–3.15 (1H, m), 3.64 (1H, m), 5.29 (1H, m), 6.75(1H, brs), 6.86 (1H, dd, J=9.0, 2.2 Hz), 7.06–7.10 (4H, m), 7.27 (1H, d,J=8.6 Hz), 7.74 (1H, brs), 12.58 (1H, brs).

EXAMPLE 11 N-cyclohexyl-1H-indazol-5-amine monohydrochloride

¹H-NMR (DMSO-d₆) δ; 1.19 (3H, m), 1.42 (2H, m), 1.60 (1H, m), 1.72 (2H,m), 1.90 (2H, m), 3.36 (1H, br), 3.62 (1H, brs), 7.47 (1H, d, J=8.8 Hz),7.68 (1H, d, J=8.8 Hz), 7.92 (1H, s), 8.20 (1H, s), 11.07 (1H, brs),13.39 (1H, brs).

EXAMPLE 12 N-tetrahydro-2H-pyran-4-yl-1H-indazol-5-amineTrifluoroacetate

Melting point: 242–245° C. (decomp.)

EXAMPLE 13 N-tetrahydro-2H-thiopyran-4-yl-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.41–1.54 (2H, m), 2.18–2.23 (2H, m), 2.64–2.75 (4H,m), 3.23–3.27 (1H, m), 5.22 (1H, d, J=8.4 Hz), 6.66 (1H, s), 6.80 (1H,dd, J=8.8 Hz), 7.68 (1H, dd, J=2.0, 8.8 Hz), 7.25 (1H, d, J=8.8 Hz),7.73 (1H, s), 12.57 (1H, brs).

EXAMPLE 14 Ethyl3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate

Melting point: 158–159° C.

EXAMPLE 15 Synthesis of N-(4-piperidinyl)-1H-indazol-5-aminedihydrochloride monohydrate (a) Synthesis ofN-(4-piperidinyl)-1H-indazol-5-amine

Ammonium formate (5.38 g) and 10% Pd—C (1.08 g) were added to a mixtureof the N-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine (5.38 g, 17.6 mmol)obtained in Example 1, (a) and ethanol (200 ml), and the resultingmixture was refluxed for 4 hours. The reaction mixture was filtered bythe use of Celite and the filtrate was concentrated. The resultingresidue was dissolved in a mixture of chloroform and methanol, followedby adding thereto hexane. The solid precipitated was collected byfiltration and dried under reduced pressure to obtainN-(4-piperidinyl)-1H-indazol-5-amine (2.29 g, 60%).

Melting point: 212–214° C.

(b) Synthesis of N-(4-piperidinyl)-1H-indazol-5-amine dihydrochloridemonohydrate

A 1N-hydrochloric acid/ether solution (5 ml) was added to a solution ofN-(4-piperidinyl)-1H-indazol-5-amine (433 mg, 2.00 mmol) in a mixture ofchloroform (4 ml) and methanol (4 ml) at room temperature and stirred atroom temperature for 30 minutes. The solid precipitated was collected byfiltration and recrystallized from a mixture of chloroform and methanolto obtain N-(4-piperidinyl)-1H-indazol-5-amine dihydrochloridemonohydrate (2.86 g, 72%).

Melting point: 263–265° C. (decomp.).

EXAMPLE 16 Synthesis of N-(1-acetyl-4-piperidinyl)-1H-indazol-5-amine

Triethylamine (0.39 ml, 2.80 mmol) was added to a solution of theN-(4-piperidinyl)-1H-indazol-5-amine (0.301 g, 1.39 mmol) obtained inExample 15, (a) in tetrahydrofuran (5 ml) at room temperature, followedby adding thereto a solution of acetyl chloride (0.12 g, 1.53 mmol) intetrahydrofuran (2 ml) at 0° C., and the resulting mixture was stirredat room temperature for 1 hour. Then, the reaction solution was pouredinto a 1N-aqueous sodium hydroxide solution and extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumchloride solution and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure and the resultingresidue was suspended in acetone and stirred. Thereafter, the solid wascollected by filtration and dried under reduced pressure to obtainN-(1-acetyl-4-piperidinyl)-1H-indazol-5-amine (0.216 g, 60%).

Melting point: 193–195° C. (decomp.).

The following compounds of Example 17 and Example 18 were synthesized bycarrying out reaction according to the method described in Example 16.

EXAMPLE 17 N-(1-propionyl-4-piperidinyl)-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 0.99 (3H, t, J=7.5 Hz), 1.13–1.31 (2H, m), 1.89–2.02(2H, m), 2.32 (2H, q, J=7.5 Hz), 2.86–2.76 (1H, m), 3.11–3.20 (1H, m),3.40–3.51 (1H, m), 3.78–3.86 (1H, m), 4.21–4.29 (1H, m), 5.21 (1H, d,J=7.1 Hz), 6.72 (1H, brs), 6.82 (1H, dd, J=2.1, 8.8 Hz), 7.26 (1H, d,J=8.8 Hz), 7.75 (1H, s), 12.59 (1H, brs).

EXAMPLE 18 N-[1-(cyclohexylcarbonyl)-4-piperidinyl]-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.09–1.40 (7H, m), 1.56–1.75 (5H, m), 1.89–2.04 (2H,m), 2.55–2.63 (1H, m), 2.73–2.83 (1H, m), 3.13–3.22 (1H, m), 3.41–3.52(1H, m), 3.87–3.94 (1H, m), 4.22–4.29 (1H, m), 5.21 (1H, d, J=8.4 Hz),6.72 (1H, d, J=2.0 Hz), 6.81 (1H, dd, J=2.0, 8.9 Hz), 7.27 (1H, d, J=9.0Hz), 7.75 (1H, s), 12.59 (1H, brs).

EXAMPLE 19 Synthesis ofN-[1-(cyclohexylmethyl)-4-piperidinyl]-1H-indazol-5-amine

A solution of theN-[1-(cyclohexylcarbonyl)-4-piperidinyl]-1H-indazol-5-amine (0.301 g,0.92 mmol) obtained in Example 18 in tetrahydrofuran (2 ml) was added toa solution of lithium aluminum hydride (0.071 g, 1.88 mmol) intetrahydrofuran (2 ml) at 0° C. and stirred at 0° C. for 1 hour. Thereaction solution was cooled on an ice-water bath, followed by addingthereto water (0.07 ml), a 2N-aqueous sodium hydroxide solution (0.14ml) and water (0.21 ml) in that order. The resulting mixture was stirredand then filtered by the use of Celite. Then, the filtrate was pouredinto a 1N-aqueous sodium hydroxide solution and extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumchloride solution and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure and the resultingresidue was suspended in ethyl acetate and stirred. Thereafter, thesolid was collected by filtration and dried under reduced pressure toobtain N-[1-(cyclohexylmethyl)-4-piperidinyl]-1H-indazol-5-amine (0.121g, 73%).

Melting point: 179–180° C.

EXAMPLE 20 Synthesis ofN-[1-(methylsulfonyl)-4-piperidinyl]-1H-indazol-5-amine

Triethylamine (0.39 ml, 2.80 mmol) was added to a solution of theN-(4-piperidinyl)-1H-indazol-5-amine (0.300 g, 1.39 mmol) obtained inExample 15, (a) in tetrahydrofuran (5 ml) at room temperature, followedby adding thereto a solution of methanesulfonyl chloride (0.175 g, 1.53mmol) in tetrahydrofuran (2 ml) at 0° C., and the resulting mixture wasstirred at room temperature for 1 hour. Then, the reaction solution waspoured into a 1N-aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was washed with a saturated aqueoussodium chloride solution and then dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:chloroform/methanol=30/1) to obtainN-[1-(methylsulfonyl)-4-piperidinyl]-1H-indazol-5-amine (0.088 g, 22%).

Melting point: 219–220° C. (decomp.).

The following compounds of Example 21 and Example 22 were synthesized bycarrying out reaction according to the method described in Example 20.

EXAMPLE 21 N-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazol-5-amine

Melting point: 182–183° C.

EXAMPLE 22 N-[1-(phenylsulfonyl)-4-piperidinyl]-1H-indazol-5-amine

Melting point: 132–136° C.

EXAMPLE 23 Synthesis ofN³-benzyl-N¹-(1H-indazol-5-yl)-N³-methyl-β-alaninamide (a) Synthesis of3-chloro-N-(1H-indazol-5-yl)propanamide

Triethylamine (1.6 ml, 30.0 mmol) was added to a solution of5-aminoindazole (2.0 g, 15.0 mmol) in tetrahydrofuran (50 ml) at roomtemperature, followed by adding thereto 3-chloropropionyl chloride (1.43ml, 15.0 mmol) at 0° C., and the resulting mixture was stirred at roomtemperature for 30 minutes. Then, the reaction solution was distilledunder reduced pressure to remove the solvent, and the resulting residuewas suspended in ethanol and stirred. Thereafter, the solid wascollected by filtration and dried under reduced pressure to obtain3-chloro-N-(1H-indazol-5-yl)propanamide (1.49 g, 44%).

Melting point: 158–160° C.

(b) Synthesis of N³-benzyl-N¹-(1H-indazol-5-yl)-N³-methyl-β-alaninamide

3-Chloro-N-(1H-indazol-5-yl)propanamide (1.10 g, 4.92 mmol) was added toN-benzylmethylamine (6.3 ml, 49.2 mmol) at room temperature and stirredat 80° C. for 1 hour. Then, the reaction solution was cooled to 0° C.and hexane was added thereto to effect suspension. The solidprecipitated was collected by filtration and purified by a silica gelcolumn chromatography (eluent: chloroform/methanol=20/1) to obtainN³-benzyl-N¹-(1H-indazol-5-yl)-N³-methyl-β-alaninamide (1.30 g, 86%).

Melting point: 140–141° C.

EXAMPLE 24 Synthesis of N³-benzyl-N¹-(1H-indazol-5-yl)-β-alaninamide

N-benzylamine (4.0 ml, 36.5 mmol) was added to a solution of3-chloro-N-(1H-indazol-5-yl)propanamide (1.70 g, 7.60 mmol) inN,N-dimethylformamide (2 ml), and the resulting mixture was stirred at80° C. for 1 hour. Then, the reaction solution was cooled to 0° C. andhexane was added thereto to effect suspension. The solid precipitatedwas collected by filtration and purified by a silica gel columnchromatography (eluent: chloroform/methanol=20/1) to obtainN³-benzyl-N¹-(1H-indazol-5-yl)-β-alaninamide (1.00 g, 45%).

¹H-NMR (DMSO-d₆) δ; 3.95 (3H, s), 6.56 (1H, d, J=16 Hz), 7.39 (1H, d,J=8.8 Hz), 7.57 (1H, d, J=16 Hz), 8.00 (1H, dd, J=2.0, 8.8 Hz), 8.23(1H, d, J=2.0 Hz), 12.42 (1H, brs).

The following compounds of Example 25 and Example 26 were synthesized bycarrying out reaction according to the method described in Example 24.

EXAMPLE 25 N¹-(1H-indazol-5-yl)-N³,N³-dimethyl-β-alaninamide

Melting point: 152–153° C.

EXAMPLE 26 N-(1H-indazol-5-yl)-3-(1-piperidinyl)propanamide

Melting point: 178–179° C.

EXAMPLE 27 Synthesis of N-(1H-indazol-5-yl)-4-methylpentanamide

To a solution of 5-aminoindazole (1.00 g, 7.51 mmol) inN,N-dimethylformamide (15 ml) were added 4-methylvaleric acid (960 mg,8.26 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidemonohydrochloride (1.72 g, 9.01 mmol), hydroxybenzotriazole (1.12 g,8.26 mmol) and triethylamine (1.7 ml, 12.0 mmol), and the resultingmixture was stirred overnight at room temperature. Then, the reactionsolution was cooled to 0° C. and a 1N-aqueous sodium hydroxide solutionwas added thereto, followed by extraction with chloroform. The organiclayer was washed with water and then a saturated aqueous sodium chloridesolution and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure and the resulting residue wasdissolved in a mixture of diethyl ether and methanol, followed by addingthereto hexane. The solid precipitated was collected by filtration anddried under reduced pressure to obtainN-(1H-indazol-5-yl)-4-methylpentanamide (1.24 g, 71%).

Melting point: 215–216° C. (decomp.)

The following compounds of Example 28 to Example 30 were synthesized bycarrying out reaction according to the method described in Example 27.

EXAMPLE 28 N-(1H-indazol-5-yl)-3-methoxypropanamide

Melting point: 173–174° C.

EXAMPLE 29 4,4,4-Trifluoro-N-(1H-indazol-5-yl)butanamide

Melting point: 243–244° C. (decomp.)

EXAMPLE 30 3-(Benzyloxy)-N-(1H-indazol-5-yl)propanamide

Melting point: 167–169° C.

EXAMPLE 31 Synthesis ofN¹-benzyl-N³-(1H-indazol-5-yl)-N¹-methyl-1,3-propanediamine

Lithium aluminum hydride (107 mg, 2.60 mmol) was added to a solution ofN³-benzyl-N¹-(1H-indazol-5-yl)-N³-methyl-β-alaninamide (200 mg, 0.973mmol) in tetrahydrofuran (30 ml) at 0° C., and the resulting mixture wasrefluxed for one and a half hours. Then, the reaction solution wascooled to 0° C. and a mixture of tetrahydrofuran (10 ml) and water (10ml) was added thereto, followed by filtration. The filtrate wasconcentrated and the resulting residue was diluted with chloroform andwashed with a 1N-aqueous sodium hydroxide solution and then a saturatedaqueous sodium chloride solution. The organic layer was dried overpotassium carbonate and distilled under reduced pressure to remove thesolvent, and the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol=20/1) to obtainN¹-benzyl-N³-(1H-indazol-5-yl)-N¹-methyl-1,3-propanediamine (138 mg,72%).

Melting point: 112–114° C.

The following compound of Example 32 was synthesized by carrying outreaction according to the method described in Example 31.

EXAMPLE 32 N¹-benzyl-N³-(1H-indazol-5-yl)-1,3-propanediamine

¹H-NMR (DMSO-d₆) δ; 1.88 (2H, dq, J=6.5, 6.5 Hz), 2.82 (2H, t, J=6.5Hz), 3.24 (2H, t, J=6.5 Hz), 3.82 (2H, s), 6.77–6.85 (2H, m), 7.23–7.35(7H, m), 7.88 (1H, brs).

EXAMPLE 33 Synthesis of 3-hydroxy-N-(1H-indazol-5-yl)propanamide

To a solution of 3-(benzyloxy)-N-(1H-indazol-5-yl)propanamide (500 mg,1.69 mmol) in methanol (100 ml) were added 1N-hydrochloric acid and 10%Pd—C (70 mg), and catalytic reduction was carried out at ordinarytemperature and atmospheric pressure. After completion of the reaction,the catalyst was filtered off and the filtrate was concentrated underreduced pressure. The resulting residue was dissolved in a mixture ofchloroform and methanol, followed by adding thereto hexane. The solidprecipitated was collected by filtration and dried under reducedpressure to obtain 3-hydroxy-N-(1H-indazol-5-yl)propanamide (201 mg,58%).

¹H-NMR (DMSO-d₆) δ; 2.47 (2H, t, J=6.4 Hz), 3.71 (2H, t, J=6.4 Hz), 7.42(1H, dd, J=1.7, 8.8 Hz), 7.46 (1H, d, J=8.8 Hz), 8.00 (1H, s), 8.14 (1H,s), 9.94 (1H, brs).

EXAMPLE 34 Synthesis of 4-(1H-indazol-5-ylamino)-4-oxobutanoic Acid

Phthalic anhydride (827 mg, 8.26 mmol) was added to a solution of5-aminoindazole (1.0 g, 7.51 mmol) in acetone (60 ml) at roomtemperature, and the resulting mixture was refluxed for 4 hours. Thesolid precipitated was collected by filtration and dried under reducedpressure to obtain 4-(1H-indazol-5-ylamino)-4-oxobutanoic acid (1.79 g,100%).

Melting point: 218–220° C. (decomp.)

EXAMPLE 35 Synthesis ofN²-benzyl-N¹-(1H-indazol-5-yl)-N²-methylglycinamide (a) Synthesis of2-chloro-N-(1H-indazol-5-yl)acetamide

Chloroacetyl chloride (3.14 ml, 39.4 mmol) was added to a solution of5-aminoindazole (5.0 g, 37.5 mmol) in tetrahydrofuran (100 ml) at roomtemperature, followed by adding thereto a solution of triethylamine(5.76 ml, 41.3 mmol) in tetrahydrofuran (30 ml) at 0° C., and theresulting mixture was stirred at 0° C. for 30 minutes. Subsequently, asaturated aqueous sodium carbonate solution and then water were added tothe reaction solution, followed by extraction with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate and distilledunder reduced pressure to remove the solvent, and the resulting residuewas suspended in ethanol and stirred, followed by filtration. To asolution of the solid collected by the filtration and dissolved in amixture of tetrahydrofuran (25 ml) and methanol (25 ml) was added a2N-aqueous lithium hydroxide solution (9.3 ml) at 0° C., and stirred atroom temperature for 30 minutes. Then, the reaction solution was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous sodium chloride solution and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure to obtain 2-chloro-N-(1H-indazol-5-yl)acetamide (1.90g, 46%).

¹H-NMR (DMSO-d₆) δ; 4.25 (2H, s), 7.41 (1H, d, J=9.0 Hz), 7.48 (1H, d,J=9.0 Hz), 8.03 (1H, s), 8.11 (1H, s), 10.29 (1H, s), 13.01 (1H, brs).

(b) Synthesis of N²-benzyl-N¹-(1H-indazol-5-yl)-N²-methylglycinamide

2-Chloro-N-(1H-indazol-5-yl)acetamide (300 mg, 1.43 mmol) was added toN-benzylmethylamine (1 ml) at room temperature and stirred at 80° C. for30 minutes. Then, ethyl acetate was added to the reaction solution toeffect suspension. The solid precipitated was collected by filtrationand purified by a silica gel column chromatography (eluent:chloroform/methanol=50/1) to obtainN²-benzyl-N¹-(1H-indazol-5-yl)-N²-methylglycinamide (163 mg, 39%).

Melting point: 159–160° C.

The following compounds of Example 36 and Example 37 were synthesized bycarrying out reaction according to the method described in Example 35.

EXAMPLE 36 N²-benzyl-N¹-(1H-indazol-5-yl)glycinamide

Melting point: 256–258° C. (decomp.)

EXAMPLE 37 N-(1H-indazol-5-yl)-2-(1-piperidinyl)acetamide

Melting point: 189–190° C.

EXAMPLE 38 Synthesis of4-[benzyl(methyl)amino]-N-(1H-indazol-5-yl)butanamide (a) Synthesis of4-chloro-N-(1H-indazol-5-yl)butanamide

Triethylamine (2.1 ml, 15 mmol) was added to a suspension of5-aminoindazole (1.00 g, 7.51 mmol) in tetrahydrofuran (10 ml) at roomtemperature, followed by adding thereto a solution of 4-chlorobutyrylchloride (1.16 g, 8.26 mmol) in tetrahydrofuran (5 ml) at 0° C., and theresulting mixture was stirred at 0° C. for 1 hour. Then, a 1N-aqueoussodium hydroxide solution was added to the reaction solution, followedby extraction with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was suspended in ethanol and stirred, followedby filtration. The solid collected by the filtration was dried underreduced pressure to obtain 4-chloro-N-(1H-indazol-5-yl)butanamide (572mg, 32%).

Melting point: 160–161° C.

(b) Synthesis of 4-[benzyl(methyl)amino]-N-(1H-indazol-5-yl)butanamide

4-Chloro-N-(1H-indazol-5-yl)butanamide (300 mg, 1.26 mmol) was added toN-benzylmethylamine (1 ml) at room temperature and stirred at 80° C. for1 hour. Then, hexane was added to the reaction solution to effectsuspension. The supernatant was removed and the resulting solid waspurified by a silica gel column chromatography (eluent:chloroform/methanol=40/1) to obtain4-[benzyl(methyl)amino]-N-(1H-indazol-5-yl)butanamide (134 mg, 33%).

Melting point: 115–117° C.

EXAMPLE 39 Synthesis of N-methyl-1H-indazol-5-amine (a) Synthesis of2,2,2-trifluoro-N-(1H-indazol-5-yl)acetamide

Trifluoroacetic anhydride (13.3 ml, 94.2 mmol) was added dropwise to asolution of 5-aminoindazole (5.00 g, 37.6 mmol) in pyridine (188 ml) at0° C. and stirred at 0° C. for 1.5 hours and then at room temperaturefor 2.5 hours. Subsequently, the reaction solution was concentrated andthe resulting residue was poured into water and extracted with ethylacetate. The organic layer was washed with 1N-hydrochloric acid and thena saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain 2,2,2-trifluoro-N-(1H-indazol-5-yl)acetamide (8.37 g, 97%).

Melting point: 249–250° C. (decomp.)

(b) Synthesis of 2,2,2-trifluoro-N-(1H-indazol-5-yl)-N-methylacetamide

Potassium carbonate (415 mg, 3.00 mmol) and methyl iodide (0.20 ml, 3.21mmol) were added to a solution of2,2,2-trifluoro-N-(1H-indazol-5-yl)acetamide (688 mg, 3.00 mmol) inN,N-dimethylformamide (4 ml) at room temperature and stirred overnightat room temperature. Then, the reaction solution was poured into waterand extracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol=99/1) to obtain2,2,2-trifluoro-N-(1H-indazol-5-yl)-N-methylacetamide (466 mg, 64%).

Melting point: 172–174° C.

(c) Synthesis of N-methyl-1H-indazol-5-amine

Potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of2,2,2-trifluoro-N-(1H-indazol-5-yl)-N-methylacetamide (3.80 g, 15.6mmol) in a mixture of methanol (95 ml) and water (16 ml) at roomtemperature, and the resulting mixture was refluxed for 1.5 hours. Then,the reaction solution was concentrated and the resulting residue waspoured into water and extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous sodium chloride solution and thendried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure to obtain N-methyl-1H-indazol-5-amine (2.30 g,100%).

Melting point: 144–146° C.

The following compound of Example 40 was synthesized by carrying outreaction according to the method described in Example 1, (a), except forusing the N-methyl-1H-indazol-5-amine obtained in Example 39, as astarting material.

EXAMPLE 40 N-(1-benzyl-4-piperidinyl)-N-methyl-1H-indazol-5-amine

Melting point: 152–154° C.

The following compound of Example 41 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the N-(1-benzyl-4-piperidinyl)-N-methyl-1H-indazol-5-amineobtained in Example 40, as a starting material.

EXAMPLE 41 N-methyl-N-(4-piperidinyl)-1H-indazol-5-amine

Melting point: 175–177° C.

EXAMPLE 42 Synthesis of 5-(4-piperidinyloxy)-1H-indazole (a) Synthesisof tert-butyl 4-(1H-indazol-5-yloxy)-1-piperidinecarboxylate

To a suspension of 1H-indazol-5-ol (134 mg, 0.999 mmol) intetrahydrofuran (4 ml) were added tert-butyl4-hydroxy-1-piperidinecarboxylate (201 mg, 0.999 mmol) andtriphenylphosphine (262 mg, 0.999 mmol) at room temperature, followed byadding thereto diethyl azodicarboxylate (0.46 ml, 1.01 mmol) at 0° C.,and the resulting mixture was stirred at 0° C. for 30 minutes and thenat room temperature for 4 hours. Subsequently, the solvent of thereaction mixture was distilled off under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate=7/3) to obtain tert-butyl4-(1H-indazol-5-yloxy)-1-piperidinecarboxylate (77 mg, 24%).

¹H-NMR (DMSO-d₆) δ; 1.42 (9H, s), 1.47–1.57 (2H, m), 1.89 (2H, m),3.16–3.24 (2H, m), 3.63–3.70 (2H, m), 4.49 (1H, m), 7.01 (1H, dd, J=9.0,2.2 Hz), 7.26 (1H, d, J=2.2 Hz), 7.42 (1H, d, J=9.0 Hz), 7.91 (1H, s),12.89 (1H, brs).

(b) Synthesis of 5-(4-piperidinyloxy)-1H-indazole

Trifluoroacetic acid (0.20 ml, 2.60 mmol) was added to a solution oftert-butyl 4-(1H-indazol-5-yloxy)-1-piperidinecarboxylate (70 mg, 0.221mmol) in methylene chloride (5 ml) at room temperature and stirredovernight at room temperature. Then, the solvent of the reactionsolution was distilled off under reduced pressure and the resultingresidue was poured into a 1N-aqueous sodium hydroxide solution andextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain 5-(4-piperidinyloxy)-1H-indazole (25 mg, 52%).

¹H-NMR (DMSO-d₆) δ; 1.49–1.59 (2H, m), 1.89–1.98 (2H, m), 2.65–2.74 (2H,m), 2.99–3.05 (2H, m), 4.37–4.42 (1H, m), 7.00 (1H, dd, J=9.0, 2.4 Hz),7.23 (1H, d, J=2.2 Hz), 7.42 (1H, d, J=9.0 Hz), 7.91 (1H, s), 12.90 (1H,brs).

The following compounds of Example 43 and Example 44 were synthesized bycarrying out reaction according to the method described in Example 42,(a).

EXAMPLE 43 5-{[1-(Methylsulfonyl)-4-piperidinyl]oxy}-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.76 (2H, m), 1.98 (2H, m), 2.88 (3H, s), 3.11 (2H,m), 3.39 (2H, m), 4.50 (1H, m), 7.05 (1H, dd, J=2.2, 8.8 Hz), 7.27 (1H,d, J=2.2 Hz), 7.42 (1H, d, J=8.8 Hz), 12.91 (1H, brs).

EXAMPLE 44 5-(Tetrahydro-2H-pyran-4-yloxy)-1H-indazole

Melting point: 151–152° C.

EXAMPLE 45

Synthesis of 5-[(4-benzyl-1-piperazinyl)carbonyl]-1H-indazole

To a solution of 1H-indazole-5-carboxylic acid (400 mg, 2.47 mmol) inN,N-dimethylformamide (8 ml) were added 1-benzylpiperazine (435 mg 2.47mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride(565 mg, 2.96 mmol), hydroxybenzotriazole (367 mg, 2.72 mmol) andtriethylamine (0.56 ml, 3.95 mmol), and the resulting mixture wasstirred overnight at room temperature. Then, a 10% aqueous potassiumhydrogensulfate solution was added to the reaction solution, followed byextraction with chloroform. A 1N-aqueous sodium hydroxide solution wasadded to the aqueous layer, followed by extraction with chloroform. Thecombined organic layer was washed with a saturated aqueous sodiumchloride solution and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:chloroform/methanol=20/1) to obtain5-[(4-benzyl-1-piperazinyl)carbonyl]-1H-indazole (624 mg, 79%).

¹H-NMR (DMSO-d₆) δ; 2.38 (4H, br), 3.50 (6H, br), 7.20–7.35 (5H, m),7.05 (1H, dd, J=2.2, 8.8 Hz), 7.34 (1H, dd, J=1.5, 8.4 Hz), 7.56 (1H, d,J=8.4 Hz), 7.81 (1H, brs), 8.13 (1H, brs), 13.23 (1H, brs).

The following compound of Example 46 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the 5-[(4-benzyl-1-piperazinyl)carbonyl]-1H-indazole obtainedin Example 45, as a starting material.

EXAMPLE 46 5-(1-Piperazinylcarbonyl)-1H-indazole

Melting point: 190–191° C.

The following compound of Example 47 was synthesized by carrying outreaction according to the method described in Example 31, except forusing the 5-[(4-benzyl-1-piperazinyl)carbonyl]-1H-indazole obtained inExample 45, as a starting material.

EXAMPLE 47 5-[(4-benzyl-1-piperazinyl)methyl]-1H-indazole

Melting point: 147–149° C.

EXAMPLE 48 Synthesis of1-benzyl-N-(1H-indazol-5-yl)-4-piperidinecarboxamide

Thionyl chloride (10.5 ml) was added to 1-benzyl-4-piperidinecarboxylicacid (4.85 g, 22.1 mmol), and the resulting mixture was refluxed for 2hours. The reaction solution was distilled under reduced pressure toremove the solvent. To a solution of the resulting residue in methylenechloride (65 ml) were added 5-aminoindazole (4.41 g, 33.2 mmol),triethylamine (1.8 ml), pyridine (30 ml) and a catalytic amount of4-dimethylaminopyridine at 0° C., and then stirred at room temperaturefor 3 hours. Then, the reaction solution was poured into a 1N-aqueoussodium hydroxide solution and extracted with chloroform. The organiclayer was washed with a saturated aqueous sodium chloride solution andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure and the resulting residue was purified by asilica gel column chromatography (eluent: chloroform/methanol=20/1) toobtain 1-benzyl-N-(1H-indazol-5-yl)-4-piperidinecarboxamide (2.2 g,30%).

¹H-NMR (DMSO-d₆) δ; 1.58–1.80 (4H, m), 1.94 (2H, br), 2.31 (1H, br),2.86 (2H, br), 3.45 (2H, s), 7.24–7.27 (5H, m), 7.39 (1H, d, J=9.2 Hz),7.44 (1H, d, J=9.2 Hz), 7.97 (1H, s), 8.12 (1H, s), 9.92 (1H, s), 12.93(1H, brs).

The following compound of Example 49 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the 1-benzyl-N-(1H-indazol-5-yl)-4-piperidinecarboxamideobtained in Example 48, as a starting material.

EXAMPLE 49 N-(1H-indazol-5-yl)-4-piperidinecarboxamide

¹H-NMR (DMSO-d₆) δ; 1.40–1.75 (4H, m), 2.30–2.55 (3H, m), 2.97 (2H, d,J=12.3 Hz), 7.40 (1H, dd, J=1.7, 8.8 Hz), 7.44 (1H, d, J=8.8 Hz), 7.98(1H, s), 8.12 (1H, s), 9.78 (1H, s), 12.94 (1H, brs).

EXAMPLE 50 Synthesis ofN-(1H-indazol-5-yl)-1-(methylsulfonyl)-4-piperidinecarboxamide

A catalytic amount of N,N-dimethylformamide and a solution of oxalyldichloride (0.367 g, 2.89 mmol) in methylene chloride (3 ml) were addedto a solution of 1-(methylsulfonyl)-4-piperidinecarboxylic acid (500 mg,2.41 mmol) in methylene chloride (7 ml), and the resulting mixture wasstirred at room temperature for three and a half hours. The reactionsolution was distilled under reduced pressure to remove the solvent, anda solution of the resulting residue in methylene chloride (5 ml) wasadded to a solution of 5-aminoindazole (322 mg, 2.42 mmol) andtriethylamine (0.67 ml, 4.8 mmol) in methylene chloride (10 ml) at 0° C.and stirred overnight at room temperature. Then, the reaction solutionwas poured into a saturated aqueous sodium hydrogencarbonate solutionand the organic solvent was distilled off under reduced pressure. Thesolid precipitated was collected by filtration and suspended inmethanol, and the resulting suspension was stirred at 50° C., followedby filtration. The solid collected by this filtration was dried underreduced pressure to obtainN-(1H-indazol-5-yl)-1-(methylsulfonyl)-4-piperidinecarboxamide (670 mg,86%).

Melting point: 291–293° C. (decomp.)

The following compound of Example 51 was synthesized by carrying outreaction according to the method described in Example 50.

EXAMPLE 51 N-(1H-indazol-5-yl)tetrahydro-2H-pyran-4-carboxamide

Melting point: 286–288° C. (decomp.)

The following compound of Example 52 was synthesized by carrying outreaction according to the method described in Example 31, except forusing the 1-benzyl-N-(1H-indazol-5-yl)-4-piperidinecarboxamide obtainedin Example 48, as a starting material.

EXAMPLE 52 5-[(1-Benzyl-4-piperidinyl)methyl]-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.13–1.30 (2H, m), 1.57 (1H, br), 1.75 (2H, br),1.88 (2H, br), 2.80 (2H, br), 2.87 (2H, dd, J=6.1, 6.1 Hz), 3.42 (2H,s), 5.33 (1H, dd, J=6.1, 6.1 Hz), 6.57 (1H, brs), 6.82 (1H, dd, J=2.2,9.0 Hz), 7.17–7.40 (6H, m), 7.71 (1H, s), 12.55 (1H, brs).

The following compound of Example 53 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the 5-[(1-benzyl-4-piperidinyl)methyl]-1H-indazol-5-amineobtained in Example 52, as a starting material.

EXAMPLE 53 N-(4-piperidinylmethyl)-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 0.95–1.15 (2H, m), 1.55–1.72 (2H, m), 2.35–2.55 (2H,m), 2.85 (2H, d, J=5.9 Hz), 2.94 (2H, d, J=12.1 Hz), 3.16 (1H, s), 5.33(1H, t, J=5.9 Hz), 6.57 (1H, d, J=2.0 Hz), 6.82 (1H, dd, J=2.0, 9.0 Hz),7.24 (1H, d, J=9.0 Hz), 7.72 (1H, s), 12.56 (1H, brs).

The following compound of Example 54 was synthesized by carrying outreaction according to the method described in Example 31, except forusing the N-(1H-indazol-5-yl)-1-(methylsulfonyl)-4-piperidinecarboxamideobtained in Example 50, as a starting material.

EXAMPLE 54N-{[1-(methylsufonyl)-4-piperidinyl]methyl}-1H-indazol-5-amine

Melting point: 262–263° C. (decomp.)

The following compound of Example 55 was synthesized by carrying outreaction according to the method described in Example 31, except forusing the N-(1H-indazol-5-yl)tetrahydro-2H-pyran-4-carboxamide obtainedin Example 51, as a starting material.

EXAMPLE 55 N-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazol-5-amine

Melting point: 293–294° C. (decomp.)

The following compounds of Example 56 and Example 57 were synthesized bycarrying out reaction according to the method described in Example 45.

EXAMPLE 56 N-(1-benzyl-4-piperidinyl)-1H-indazole-5-carboxamide

Melting point: 240–242° C. (decomp.)

EXAMPLE 57 N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide

Melting point: 285–286° C.

¹H-NMR (DMSO-d₆) δ; 1.58 (2H, dddd, J=4.3, 11.9, 11.9, 11.9 Hz),1.72–1.82 (2H, m), 3.38 (2H, ddd, J=2.0, 11.9, 11.9 Hz), 3.80–3.93 (2H,m), 3.9–4.10 (1H, m), 7.55 (1H, d, J=8.8 Hz), 7.84 (1H, dd, J=1.7, 8.8Hz), 8.30 (1H, s), 8.32 (1H, s), 13.26 (1H, s).

The following compound of Example 58 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the N-(1-benzyl-4-piperidinyl)-1H-indazole-5-carboxamideobtained in Example 56, as a starting material.

EXAMPLE 58 N-(4-piperidinyl)-1H-indazole-5-carboxamide

Melting point: 273–275° C. (decomp.)

The following compound of Example 59 was synthesized by carrying outreaction according to the method described in Example 20, except forusing the N-(4-piperidinyl)-1H-indazole-5-carboxamide obtained inExample 58, as a starting material.

EXAMPLE 59N-[1-(methylsulfonyl)-4-piperidinyl]-1H-indazole-5-carboxamide

¹H-NMR (DMSO-d₆) δ; 1.63 (2H, m), 2.86 (2H, m), 3.55 (2H, m), 3.95 (1H,m), 7.57 (1H, d, J=8.8 Hz), 7.82 (1H, d, J=8.8 Hz), 8.20 (1H, s), 8.32(1H, s), 8.35 (1H, d, J=9.6 Hz), 13.26 (1H, s).

The following compounds of Example 60 and Example 61 were synthesized bycarrying out reaction according to the method described in Example 27.

EXAMPLE 60 2-(1-Benzyl-4-piperidinyl)-N-(1H-indazol-5-yl)acetamide

Melting point: 195–197° C.

EXAMPLE 61 2-(1-Benzyl-4-piperidinylidene)-N-(1H-indazol-5-yl)acetamide

Melting point: 169–172° C.

The following compound of Example 62 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the 2-(1-benzyl-4-piperidinyl)-N-(1H-indazol-5-yl)acetamideobtained in Example 60, as a starting material.

EXAMPLE 62 N-(1H-indazol-5-yl)-2-(4-piperidinyl)acetamide

¹H-NMR (DMSO-d₆) δ; 1.08 (2H, m), 1.56 (2H, m), 1.82 (1H, m), 2.18 (2H,d, J=7.2 Hz), 2.42 (2H, m), 2.86 (2H, m), 7.40 (1H, dd, J=1.6, 8.8 Hz),7.43 (1H, d, J=8.8 Hz), 7.98 (1H, s), 8.11 (1H, s), 9.84 (1H, s), 12.95(1H, s).

The following compound of Example 63 was synthesized by carrying outreaction according to the method described in Example 19, except forusing the 2-(1-benzyl-4-piperidinyl)-N-(1H-indazol-5-yl)acetamideobtained in Example 60, as a starting material.

EXAMPLE 63 N-[2-(1-benzyl-4-piperidinyl)ethyl]-1H-indazol-5-amine

Melting point: 117–118° C.

The following compound of Example 64 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the N-[2-(1-benzyl-4-piperidinyl)ethyl]-1H-indazol-5-amineobtained in Example 63, as a starting material.

EXAMPLE 64 N-[2-(4-piperidinyl)ethyl]-1H-indazol-5-amine

Melting point: 184–186° C. (decomp.)

EXAMPLE 65 Synthesis ofN-(1H-indazol-5-ylmethyl)-4-piperidinecarboxamide (a) Synthesis of1-(1H-indazol-5-yl)methanamine

A solution of 1H-indazole-5-carbonitrile (100 mg, 0.699 mmol) intetrahydrofuran (4 ml) was added to a solution of lithium aluminumhydride (53 mg, 1.40 mmol) in tetrahydrofuran (4 ml) at roomtemperature, and the resulting mixture was refluxed for 2 hours.Subsequently, water (0.053 ml), a 2N-aqueous lithium hydroxide solution(0.106 ml) and water (0.212 ml) were added in that order to the reactionsolution and stirred, followed by filtration. The solvent was distilledoff under reduced pressure and the residue was dried under reducedpressure to obtain 1-(1H-indazol-5-yl)methanamine (97 mg, 94%).

(b) Synthesis of tert-butyl4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate

To a solution of 1-(1H-indazol-5-yl)methanamine (291 mg) inN,N-dimethylformamide (8 ml) were added1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (507 mg, 2.21 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (578mg, 3.02 mmol) and hydroxybenzotriazole (229 mg, 2.21 mmol), and theresulting mixture was stirred at room temperature for 14 hours.Subsequently, a saturated aqueous sodium hydrogencarbonate solution andthen water were added to the reaction solution, followed by extractionwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent. Theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol=40/1). To a solution of the resulting solidin a mixture of methanol (1 ml) and tetrahydrofuran (1 ml) was added a2N-aqueous lithium hydroxide solution (0.68 ml), and the resultingmixture was stirred at room temperature for 30 minutes. Then, thereaction solution was poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand distilled under reduced pressure to remove the solvent. Theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol=30/1) to obtain tert-butyl4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate (179mg).

(c) Synthesis of N-(1H-indazol-5-ylmethyl)-4-piperidinecarboxamide

A 4N-hydrochloric acid/dioxane solution (2.0 ml) was added to tert-butyl4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate (160mg, 0.446 mmol), and the resulting mixture was stirred at roomtemperature for 2 hours. Then, the reaction solution was poured into asaturated aqueous sodium hydrogencarbonate solution and extracted withchloroform. The organic layer was dried over anhydrous magnesium sulfateand distilled under reduced pressure to remove the solvent. Theresulting residue was recrystallized from a mixture of ethanol anddiethyl ether to obtainN-(1H-indazol-5-ylmethyl)-4-piperidinecarboxamide (10 mg, 9%).

¹H-NMR (DMSO-d₆) δ; 1.42 (2H, m), 2.22 (1H, m), 2.42 (2H, m), 3.46 (2H,m), 4.30 (2H, d, J=5.9 Hz), 7.23 (1H, d, J=8.7 Hz), 7.45 (1H, d, J=8.7Hz), 7.55 (1H, s), 8.01 (1H, s), 8.23 (1H, t, J=5.9 Hz), 13.00 (1H, s).

EXAMPLE 66 Synthesis of 5-(4-benzyl-1-piperazinyl)-1H-indazole (a)Synthesis of5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole

To a solution of the 5-bromo-1-tetrahydro-2H-pyran-2-yl-1H-indazole (250mg, 0.889 mmol) obtained in Reference Example 5 in toluene (12 ml) wereadded 1-benzylpiperazine (0.24 ml, 1.35 mmol) and sodium tert-butoxide(128 mg, 1.33 mmol) at room temperature. After deaeration,bis(tri-o-tolylphosphine)-palladium(II) dichloride (70 mg, 0.0891 mmol)was added thereto and the resulting mixture was stirred at 75° C. forthree and a half hours. Then, the reaction solution was poured intowater and extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure and the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/ethyl acetate=5/2) to obtain5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (183mg, 55%).

(b) Synthesis of 5-(4-benzyl-1-piperazinyl)-1H-indazole

Acetic acid (2.6 ml) and water (0.7 ml) were added to a solution of5-(4-benzyl-1-piperazinyl)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (100mg, 0.266 mmol) in tetrahydrofuran (1.3 ml) at room temperature andstirred 80° C. for 7 hours. Then, the reaction solution was concentratedand the resulting residue was diluted with ethyl acetate and washed witha saturated aqueous sodium hydrogencarbonate solution and then asaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent, and the resulting residue was purified by athin-layer chromatography (eluent: chloroform/methanol=95/5) to obtain5-(4-benzyl-1-piperazinyl)-1H-indazole (37 mg, 47%).

Melting point: 196–198° C. (decomp.)

The following compound of Example 67 was synthesized by carrying outreaction according to the method described in Example 66.

EXAMPLE 67 5-(4-Morpholinyl)-1H-indazole

¹H-NMR (DMSO-d₆) δ; 3.02–3.05 (4H, m), 3.73–3.76 (4H, m), 7.08 (1H, m),7.18 (1H, dd, J=9.2, 2.2 Hz), 7.41 (1H, d, J=9.0 Hz), 7.89 (1H, s),12.80 (1H, brs).

The following compound of Example 68 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the 5-(4-benzyl-1-piperazinyl)-1H-indazole obtained in Example66, as a starting material.

EXAMPLE 68 5-(1-Piperazinyl)-1H-indazole

¹H-NMR (DMSO-d₆) δ; 2.85–2.86 (2H, m), 2.95–2.98 (2H, m), 3.06 (1H, m),7.05 (1H, brs), 7.14–7.16 (1H, m), 7.39 (1H, d, J=9.0 Hz), 7.87 (1H, s),12.79 (1H, brs).

EXAMPLE 69 Synthesis of 2-(1H-indazol-5-ylamino)-N,N-dimethylbenzamide

To a solution of 2-(1H-indazol-5-ylamino)benzoic acid (80 mg, 0.316mmol) in N,N-dimethylformamide (0.5 ml) were added1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (73 mg,0.379 mmol), hydroxybenzotriazole (58 mg, 0.379 mmol) and a 40%-aqueousdimethylamine solution (107 mg, 0.948 mmol), and the resulting mixturewas stirred at room temperature for 4 hours. Then, a 5%-aqueous sodiumhydrogencarbonate solution was added to the reaction solution, followedby extraction with a mixed solvent of ethyl acetate and toluene. Theorganic layer was washed with a 5%-aqueous sodium hydrogencarbonatesolution and then a 5%-aqueous sodium chloride solution and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure and the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate/methanol=1/1/0.05) toobtain 2-(1H-indazol-5-ylamino)-N,N-dimethylbenzamide (59 mg, 67%).

Melting point: 234–235° C. (decomp.)

The following compounds of Example 70 to Example 73 were synthesized bycarrying out reaction according to the method described in Example 1,except for using 1H-indazol-4-amine as a starting material.

EXAMPLE 70 N-(1-benzyl-4-piperidinyl)-1H-indazol-4-amine

¹H-NMR (DMSO-d₆) δ; 1.45–1.57 (2H, m), 1.93–2.01 (2H, m), 2.05–2.13 (2H,m), 2.80–2.87 (2H, m), 3.32–3.42 (1H, m), 3.49 (2H, s), 5.90 (1H, d,J=8.1 Hz), 6.05 (1H, d, J=7.9 Hz), 6.62 (1H, d, J=7.9 Hz), 7.03 (1H, t,J=7.9 Hz), 7.22–7.36 (5H, m), 8.18 (1H, br), 12.64 (1H, b).

EXAMPLE 71 N-[1-(2-phenethyl)-4-piperidinyl]-1H-indazol-4-amine

Melting point: 196–198° C. (decomp.)

EXAMPLE 72 N-(1-benzyl-4-piperidinyl)-1H-indazol-4-amine dihydrochloride

Melting point: 257–260° C. (decomp.)

EXAMPLE 73 N-[1-(2-phenethyl)-4-piperidinyl]-1H-indazol-4-aminedimethanesulfonate

Melting point: 213–215° C. (decomp.)

The following compounds of Example 74 and Example 75 were synthesized bycarrying out reaction according to the method described in Example 15,except for using N-(1-benzyl-4-piperidinyl)-1H-indazol-4-amine as astarting material.

EXAMPLE 74 N-(4-piperidinyl)-1H-indazol-4-amine

¹H-NMR (DMSO-d₆) δ; 1.57–1.69 (2H, m), 2.05–2.12 (2H, m), 2.88–2.98 (2H,m), 3.23–3.31 (2H, m), 3.60–3.71 (1H, m), 6.10 (1H, d, J=8.1 Hz), 6.12(1H, d, J=7.5 Hz), 6.67 (1H, d, J=8.0 Hz), 7.06 (1H, dd, J=7.5, 8.0 Hz),8.21 (1H, d, J=12 Hz), 12.7 (1H, b).

EXAMPLE 75 N-(4-piperidinyl)-1H-indazol-4-amine dihydrochloride

Melting point: 270–271° C.

The following compounds of Example 76 and Example 77 were synthesized bycarrying out reaction according to the method described in Example 1,except for using 1H-indazol-6-amine as a starting material.

EXAMPLE 76 N-(1-benzyl-4-piperidinyl)-1H-indazol-6-amine

¹H-NMR (DMSO-d₆) δ; 1.35–1.47 (2H, m), 1.89–1.97 (2H, m), 2.04–2.14 (2H,m), 2.75–2.83 (2H, m), 3.17–3.27 (1H, m), 3.48 (2H, s), 5.66 (1H, d,J=7.5 Hz), 6.34 (1H, br), 6.52 (1H, dd, J=1.8, 8.9 Hz), 7.21–7.34 (5H,m), 7.36 (1H, dd, J=8.9 Hz), 7.71 (1H, s), 12.26 (1H, br).

EXAMPLE 77 N-(1-benzyl-4-piperidinyl)-1H-indazol-6-amine dihydrochloride

¹H-NMR (DMSO-d₆) δ; 1.88–2.19 (4H, m), 2.95–3.43 (4H, m), 3.55–3.86 (1H,m), 4.26–4.35 (2H, m), 6.80–7.10 (2H, m), 7.44–7.48 (3H, m), 7.58–7.68(3H, m), 8.06–8.09 (1H, m), 11.0 (1H, br).

The following compounds of Example 78 and Example 79 were synthesized bycarrying out reaction according to the method described in Example 15,except for using N-(1-benzyl-4-piperidinyl)-1H-indazol-6-amine as astarting material.

EXAMPLE 78 N-(4-piperidinyl)-1H-indazol-6-amine

Melting point: 196–197° C. (decomp.)

EXAMPLE 79 N-(4-piperidinyl)-1H-indazol-6-amine dihydrochloride

¹H-NMR (DMSO-d₆) δ; 1.74–1.88 (2H, m), 2.05–2.13 (2H, m), 2.89–3.02 (2H,m), 3.28–3.36 (2H, m), 3.65–3.74 (1H, m), 6.93 (1H, br), 7.05 (1H, br),7.68 (1H, d, J=8.9 Hz), 7.95 (1H, s), 8.90 (1H, br), 9.10 (1H, br),13.30 (1H, br).

The following compounds of Example 80 to Example 82 were synthesized bycarrying out reaction according to the method described in Example 1,except for using 1-methyl-1H-indazol-5-amine as a starting material.

EXAMPLE 80 N-(1-benzyl-4-piperidinyl)-1-methyl-1H-indazol-5-amine

Melting point: 116–117° C.

EXAMPLE 811-Methyl-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-indazol-5-amineN-(1-benzyl-4-piperidinyl)-1H-benzimidazol-5-amine

¹H-NMR (DMSO-d₆) 67; 1.31–1.41 (2H, m), 1.92–1.98 (2H, m), 2.06–2.13(2H, m), 2.48–2.53 (2H, m), 2.69–2.75 (2H, m), 2.88–2.92 (2H, m), 3.16(1H, m), 3.91 (3H, s), 5.17 (1H, d, J=8.3 Hz), 6.64 (1H, d, J=1.8 Hz),6.85 (1H, dd, J=9.0, 1.8 Hz), 7.14–7.29 (5H, m), 7.33 (1H, d, J=9.0 Hz),7.68 (1H, s).

EXAMPLE 82 N-(1-benzyl-4-piperidinyl)-1-methyl-1H-indazol-5-aminedihydrochloride N-(1-benzyl-4-piperidinyl)-1H-benzimidazol-5-amine

¹H-NMR (DMSO-d₆) δ; 2.12 (4H, m), 2.71–3.66 (5H, m), 4.05 (3H, s),4.05–4.41 (2H, m), 7.43–7.57 (5H, m), 7.67–7.79 (2H, m), 8.13 (1H, s),10.87 (1H, brs).

The following compounds of Example 83 and Example 84 were synthesized bycarrying out reaction according to the method described in Example 15,except for using N-(1-benzyl-4-piperidinyl)-1-methyl-1H-indazol-5-amineas a starting material.

EXAMPLE 83 1-Methyl-N-(4-piperidinyl)-1H-indazol-5-amine

Melting point: 111–113° C.

EXAMPLE 84 1-Methyl-N-(4-piperidinyl)-1H-indazol-5-amine dihydrochloride

¹H-NMR (DMSO-d₆) δ; 1.92–2.12 (4H, m), 2.86–2.90 (2H, m), 3.32–3.36 (2H,m), 3.71 (1H, m), 7.44 (1H, brs), 7.67–7.69 (1H, m), 7.88 (1H, m), 8.17(1H, s), 8.68 (1H, m), 9.13 (1H, m).

The following compounds of Example 85 and Example 86 were synthesized bycarrying out reaction according to the method described in Example 1,except for using 2-methyl-2H-indazol-5-amine as a starting material.

EXAMPLE 85 N-(1-benzyl-4-piperidinyl)-2-methyl-2H-indazol-5-amine

Melting point: 108–110° C.

EXAMPLE 86 N-(1-benzyl-4-piperidinyl)-2-methyl-2H-indazol-5-aminedihydrochloride

¹H-NMR (DMSO-d₆) δ; 2.12 (4H, m), 2.93–3.65 (5H, m), 4.17 (3H, s),4.17–4.41 (2H, m), 7.24–7.28 (1H, m), 7.43–7.56 (5H, m), 7.69–7.73 (2H,m), 8.44 (1H, s), 10.84 (1H, brs).

The following compounds of Example 87 and Example 88 were synthesized bycarrying out reaction according to the method described in Example 15,except for using N-(1-benzyl-4-piperidinyl)-2-methyl-2H-indazol-5-amineas a starting material.

EXAMPLE 87 2-Methyl-N-(4-piperidinyl)-2H-indazol-5-amine

Melting point: 144–147° C.

EXAMPLE 88 2-Methyl-N-(4-piperidinyl)-2H-indazol-5-amine dihydrochloride

¹H-NMR (DMSO-d₆) δ; 1.95–2.26 (4H, m), 2.86–2.90 (2H, m), 3.32–3.36 (2H,m), 3.71 (1H, m), 4.18 (3H, s), 7.30–7.33 (1H, m), 7.73–7.86 (1H, m),8.48 (1H, s), 8.89 (1H, m), 9.20 (1H, m).

The following compounds of Example 89 to Example 91 were synthesized bycarrying out reaction according to the method described in Example 1,except for using 3-methyl-1H-indazol-5-amine as a starting material.

EXAMPLE 89 N-(1-benzyl-4-piperidinyl)-3-methyl-1H-indazol-5-amine

Melting point: 160–162° C.

EXAMPLE 903-Methyl-N-[1-(2-phenylethyl)-4-piperidinyl]-1H-indazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.31–1.41 (2H, m), 1.92–1.95 (2H, m), 2.08–2.14 (2H,m), 2.36 (3H, s), 2.48–2.53 (2H, m), 2.70–2.75 (2H, m), 2.88–2.92 (2H,m), 3.16 (1H, m), 5.06 (1H, d, J=8.3 Hz), 6.58 (1H, s), 6.78 (1H, dd,J=8.8, 2.0 Hz), 7.15–7.29 (6H, m), 12.11 (1H, brs).

EXAMPLE 91 N-(1-benzyl-4-piperidinyl)-3-methyl-1H-indazol-5-aminedihydrochloride

¹H-NMR (DMSO-d₆) 67; 2.13 (4H, m), 2.49 (3H, s), 2.92 (2H, m), 3.27–3.86(3H, m), 4.23–4.41 (2H, m), 7.43–7.81 (9H, m), 10.86 (1H, brs).

The following compounds of Example 92 and Example 93 were synthesized bycarrying out reaction according to the method described in Example 15,except for using N-(1-benzyl-4-piperidinyl)-3-methyl-1H-indazol-5-amineas a starting material.

EXAMPLE 92 3-Methyl-N-(4-piperidinyl)-1H-indazol-5-amine

Melting point: 175–177° C.

EXAMPLE 93 3-Methyl-N-(4-piperidinyl)-1H-indazol-5-amine dihydrochloride

¹H-NMR (DMSO-d₆) δ; 1.92–2.03 (4H, m), 2.50 (3H, s), 2.70–2.95 (2H, m),3.33–3.88 (3H, m), 7.41–7.85 (3H, m), 8.86–8.92 (1H, m), 9.19 (1H, m).

The following compound of Example 94 was synthesized by carrying outreaction according to the method described in Example 1, (a), except forusing 1H-benzimidazol-5-amine as a starting material.

EXAMPLE 94 N-(1-benzyl-4-piperidinyl)-1H-benzimidazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.36–1.39 (2H, m), 1.90–1.93 (2H, m), 2.03–2.10 (2H,m), 2.76–2.80 (2H, m), 3.19 (1H, m), 3.46 (2H, s), 5.21 (1H, brs),6.53–6.59 (2H, m), 7.23–7.34 (6H, m), 7.84 (1H, brs), 11.81 (1H, brs).

The following compound of Example 95 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using N-(1-benzyl-4-piperidinyl)-1H-benzimidazol-5-amine as astarting material.

EXAMPLE 95 N-(4-piperidinyl)-1H-benzimidazol-5-amine

¹H-NMR (DMSO-d₆) δ; 1.14–1.27 (2H, m), 1.86–1.89 (2H, m), 2.49–2.56 (2H,m), 2.92–2.98 (2H, m), 3.29 (1H, m), 5.15 (1H, brs), 6.53–6.66 (2H, m),7.26 (1H, d, J=8.4 Hz), 7.84 (1H, brs), 11.81 (1H, brs).

The following compound of Example 96 was synthesized by carrying outreaction according to the method described in Example 1, (a), except forusing 1,2-benzisoxazol-5-amine as a starting material.

EXAMPLE 96 N-(1-benzyl-4-piperidinyl)-1,2-benzisoxazol-5-amine

Melting point: 89–90° C.

The following compound of Example 97 was synthesized by carrying outreaction according to the method described in Example 1, (a), except forusing 5-amino-1,3-dihydro-2H-benzimidazol-2-one as a starting material.

EXAMPLE 975-[(1-Benzyl-4-piperidinyl)amino]-1,3-dihydro-2H-benzimidazol-2-one

¹H-NMR (DMSO-d₆) δ; 1.32 (2H, m), 1.84 (2H, m), 2.02 (2H, m), 2.74 (2H,m), 3.06 (1H, m), 3.44 (2H, s), 4.94 (1H, d, J=8.6 Hz), 6.20 (1H, d,J=8.1 Hz), 6.20 (1H, s), 6.59 (1H, d, J=8.1 Hz), 7.25 (5H, m), 10.03(1H, s), 10.17 (1H, s).

The following compound of Example 98 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using5-[(1-benzyl-4-piperidinyl)amino]-1,3-dihydro-2H-benzimidazol-2-one as astarting material.

EXAMPLE 98 5-(4-Piperidinylamino)-1,3-dihydro-2H-benzimidazol-2-one

¹H-NMR (DMSO-d₆) δ; 1.14 (2H, m), 1.80 (2H, m), 2.48 (2H, m), 2.89 (2H,m), 3.11 (1H, brs), 4.92 (1H, d, J=7.9 Hz), 6.20 (1H, d, J=8.1 Hz), 6.20(1H, s), 6.59 (1H, d, J=8.1 Hz), 10.03 (1H, s), 10.17 (1H, s).

EXAMPLE 99 Synthesis ofN-(1-propylpiperidin-4-yl)-1H-indazole-5-carboxamide

Acetic acid (0.048 ml) was added to a solution of theN-(4-piperidinyl)-1H-indazole-5-carboxamide (40.0 mg, 0.164 mmol)obtained in Example 58 in methanol (1.2 ml), and the resulting solutionwas maintained at room temperature for 30 minutes. Propionaldehyde (48.0mg, 0.826 mmol) was added to the solution and the resulting mixture wasmaintained at room temperature for another 2 hours. Then, a solution ofsodium cyanoborohydride (51.5 mg, 0.820 mmol) in methanol (3.0 ml) wasadded dropwise thereto, and the resulting mixture was stirred for 18hours while being maintained at room temperature. A 1N-aqueous sodiumhydroxide solution (0.8 ml) was added to the reaction solution, and theresulting mixture was stirred while being maintained at roomtemperature, and then was concentrated to dryness. The resulting crudeproduct residue was purified by a silica gel column chromatography(eluent: chloroform/methanol/aqueous ammonia=20/1/0.1) to obtainN-(1-propylpiperidin-4-yl)-1H-indazole-5-carboxamide (31 mg, 46%).

MS: m/z=287 (M+1)

The following compounds of Example 100 to Example 114 were synthesizedby carrying out reaction according to the method described in Example99.

EXAMPLE 100 N-(1-butylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=301 (M+1)

EXAMPLE 101 N-(1-isobutylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=301 (M+1)

EXAMPLE 102 N-(1-isopentylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=315 (M+1)

EXAMPLE 103N-[1-(3,3-dimethylbutyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z 329 (M+1)

EXAMPLE 104 N-(1-cyclobutylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=299 (M+1)

EXAMPLE 105 N-(1-cyclopentylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=313 (M+1)

EXAMPLE 106 N-(1-cyclohexylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=327 (M+1)

EXAMPLE 107N-(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=329 (M+1)

EXAMPLE 108 N-(1′-methyl-1,4′-piperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=342 (M+1)

EXAMPLE 109 N-(1-cycloheptylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=341 (M+1)

EXAMPLE 110N-[1-(cyclopropylmethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=299 (M+1)

EXAMPLE 111N-[1-(cyclohexylmethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=341 (M+1)

EXAMPLE 112N-[1-(2-phenylethyl)piperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=349 (M+1)

EXAMPLE 113 N-(1-methylpiperidin-4-yl)-1H-indazole-5-carboxamide

¹H-NMR (DMSO-d₆) δ; 1.53–1.65 (2H, m), 1.73–1.81 (2H, m), 1.89–1.98 (2H,m), 2.16 (3H, s), 2.73–2.81 (2H, m), 3.69–3.80 (1H, m), 7.55 (1H, d,J=8.8 Hz), 7.84 (1H, dd, J=8.8, 1.5 Hz), 8.20 (1H, s), 8.22 (1H, d,J=7.6 Hz), 8.32 (1H, s), 13.25 (1H, br).

EXAMPLE 114 N-(1-isopropylpiperidin-4-yl)-1H-indazole-5-carboxamide

¹H-NMR (DMSO-d₆) δ; 0.97 (6H, d, J=6.6 Hz), 1.47–1.59 (2H, m), 1.75–1.84(2H, m), 2.12–2.21 (2H, m), 2.69 (1H, q, J=6.6 Hz), 2.76–2.83 (2H, m),3.68–3.80 (1H, m), 7.55 (1H, d, J=8.9 Hz), 7.84 (1H, dd, J=8.9, 1.7 Hz),8.20 (1H, s), 8.21 (1H, d, J=7.6 Hz), 8.31 (1H, s), 13.25 (1H, br).

EXAMPLE 115 Synthesis ofN-[1-(but-2-enyl)piperidin-4-yl]-1H-indazole-5-carboxamide

Potassium carbonate (55.0 mg, 0.398 mmol) and 1-chloro-2-butene (17.8mg, 0.197 mmol) were added to a solution of theN-(4-piperidinyl)-1H-indazole-5-carboxamide (40.0 mg, 0.164 mmol)obtained in Example 58 in N,N-dimethylformamide (1.2 ml), and theresulting mixture was stirred for 20 hours while being maintained atroom temperature. The reaction solution was filtered and the filtratewas concentrated to dryness. The resulting crude product residue waspurified by a silica gel column chromatography (eluent:chloroform/methanol/aqueous ammonia=20/1/0.1) to obtainN-[1-(but-2-enyl)piperidin-4-yl]-1H-indazole-5-carboxamide (26 mg, 54%).

MS: m/z=299 (M+1)

The following compounds of Example 116 to Example 134 were synthesizedby carrying out reaction according to the method described in Example115.

EXAMPLE 116N-[1-(3-methylbut-2-enyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=313 (M+1)

EXAMPLE 117 N-(1-prop-2-ynylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=283 (M+1)

EXAMPLE 118N-[1-(2-hydroxyethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=289 (M+1)

EXAMPLE 119N-[1-(2-hydroxypropyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=303 (M+1)

EXAMPLE 120N-[1-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=317 (M+1)

EXAMPLE 121N-[1-(3-hydroxypropyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=303 (M+1)

EXAMPLE 122N-[1-(2-methoxyethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=303 (M+1)

EXAMPLE 123N-{1-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=347 (M+1)

EXAMPLE 124N-[1-(2-phenoxyethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=365 (M+1)

EXAMPLE 125N-[1-(2-fluoroethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=291 (M+1)

EXAMPLE 126N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=327 (M+1)

EXAMPLE 127N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=341 (M+1)

EXAMPLE 128 N-[1-(cyanomethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=284 (M+1)

EXAMPLE 129 N-[1-(2-cyanoethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=298 (M+1)

EXAMPLE 130N-[1-(2-amino-2-oxoethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=302 (M+1)

EXAMPLE 131 N-[1-(2-oxopropyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=301 (M+1)

EXAMPLE 132N-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-1H-indazole-5-carboxamide

MS: m/z=316 (M+1)

EXAMPLE 133N-[1-(cyclobutylmethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=313 (M+1)

EXAMPLE 134N-[1-(tetrahydro-2H-pyran-2-ylmethyl)piperidin-4-yl]-1H-indazole-5-carboxamide

MS: m/z=343 (M+1)

The following compounds of Examples 135 and 136 were synthesized bycarrying out reaction according to the method described in Example 45.

EXAMPLE 135 N-(1-phenylpiperidin-4-yl)-1H-indazole-5-carboxamide

MS: m/z=321 (M+1)

EXAMPLE 136 N-(1-benzylpyrrolidin-3-yl)-1H-indazole-5-carboxamide

Melting point: 187–189° C.

The following compound of Example 137 was synthesized by carrying outreaction according to the method described in Example 15, (a), exceptfor using the N-(1-benzylpyrrolidin-3-yl)-1H-indazole-5-carboxamideobtained in Example 136, as a starting material.

EXAMPLE 137 N-(3-pyrrolidinyl)-1H-indazole-5-carboxamide

¹H-NMR (DMSO-d₆) δ; 1.63–1.73 (1H, m), 1.93–2.02 (1H, m), 2.65–2.78 (2H,m), 2.89–2.98 (2H, m), 4.28–4.37 (1H, m), 7.55 (1H, d, J=8.9 Hz), 7.85(1H, dd, J=1.4, 8.9 Hz), 8.20 (1H, s), 8.31 (1H, d, J=7.3 Hz), 8.33 (1H,s), 13.2 (1H, br).

EXAMPLE 138 Synthesis ofN-(1-benzylpiperidin-3-yl)-1H-indazole-5-carboxamide (a) Synthesis ofethyl 1-benzyl-3-piperidinecarboxylate

Benzyl chloride (5.5 ml, 47.8 mmol) and potassium carbonate (8.3 g, 60.1mmol) were added to a solution of ethyl 3-piperidinecarboxylate (6.55 g,40.0 mmol) in N,N-dimethylformamide (20 ml), and the resulting mixturewas stirred at 100° C. for 10 hours. After completion of the reaction,the reaction solution was filtered and the filtrate was subjected toazeotropic concentration with toluene. The resulting residue waspurified by a silica gel column chromatography (eluent: n-hexane/ethylacetate=20/1) to obtain ethyl 1-benzyl-3-piperidinecarboxylate (7.45 g,75.3%).

(b) Synthesis of 1-benzyl-3-piperidinecarboxylic acid

A 4N-aqueous sodium hydroxide solution (15 ml) was added to a solutionof ethyl 1-benzyl-3-piperidinecarboxylate (7.00 g, 28.3 mmol) in amixture of tetrahydrofuran (30 ml) and 1,4-dioxane (30 ml), and theresulting mixture was stirred at room temperature for 4 hours. After a4N-aqueous sodium hydroxide solution (15 ml) was added again, theresulting mixture was stirred overnight at room temperature. Aftercompletion of the reaction, the reaction solution was neutralized by theaddition of 2N-hydrochloric acid (15 ml) under ice-cooling and theresulting mixture was subjected to azeotropic concentration withtoluene. The residue was suspended in ethanol, followed by filtration,and the filtrate was concentrated to obtain1-benzyl-3-piperidinecarboxylic acid (6.3 g, 100%).

(c) Synthesis of tert-butyl 1-benzyl-3-piperidinylcarbamate

Triethylamine (0.38 ml, 2.73 mmol) and diphenylphosphoryl azide (0.692g, 2.52 mmol) were added to a solution of1-benzyl-3-piperidinecarboxylic acid (0.501 g, 2.28 mmol) in toluene (10ml), and the resulting mixture was stirred for 2 hours with heatingunder reflux. The solvent was distilled off under reduced pressure and asolution of the resulting residue in tert-butanol (10 ml) was stirredfor 4 hours with heating under reflux. The solvent was distilled offunder reduced pressure and a 1N-aqueous sodium hydroxide solution wasadded to the residue, followed by extraction with ethyl acetate (threetimes). The extract solution was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure and the residue waspurified by a silica gel chromatography (eluent: hexane/ethylacetate=5/1) to obtain tert-butyl 1-benzyl-3-piperidinylcarbamate (0.475g, 72%).

(d) Synthesis of 1-benzyl-3-piperidinamine dihydrochloride

A 4N-hydrochloric acid/1,4-dioxane solution (4 ml) was added to asolution of tert-butyl 1-benzyl-3-piperidinylcarbamate (0.448 g, 1.54mmol) in tetrahydrofuran (4 ml) and stirred overnight. After the solventwas distilled off under reduced pressure, diethyl ether was added to theresidue to precipitate a solid, and the supernatant was decanted andthen dried under reduced pressure to obtain 1-benzyl-3-piperidinaminedihydrochloride (0.384 g, 95%).

(e) Synthesis of N-(1-benzylpiperidin-3-yl)-1H-indazole-5-carboxamide

The 1H-indazole-5-carboxylic acid (0.225 g, 1.39 mmol) obtained inReference Example 1, triethylamine (0.57 ml, 4.1 mmol),1-hydroxybenztriazole (0.222 g, 1.64 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.314g, 1.64 mmol) were added to a solution of 1-benzyl-3-piperidinaminedihydrochloride (0.360 g, 1.37 mmol) in N,N-dimethylformamide (5 ml) andstirred overnight. The resulting mixture was added to a 1N-aqueoussodium hydroxide solution and extracted three times with ethyl acetate,and the extract solution was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure and the residue waspurified by a silica gel chromatography (eluent:chloroform/methanol=20/1) to obtainN-(1-benzylpiperidin-3-yl)-1H-indazole-5-carboxamide (0.384 g, 83%).

Melting point: 203–204° C.

EXAMPLE 139 Synthesis of N-(3-piperidinyl)-1H-indazole-5-carboxamide

Ammonium formate (0.363 g) and 10% Pd—C (0.074 g) were added to asuspension of the N-(1-benzylpiperidin-3-yl)-1H-indazole-5-carboxamide(0.357 g, 1.06 mmol) obtained in Example 138 in ethanol (10 ml), and theresulting mixture was stirred for 4 hours with heating under reflux. Theresulting solution was filtered by the use of Celite and then thesolvent was distilled off from the filtrate to obtain a solid. The solidobtained was suspended in ethyl acetate, stirred to be washed, collectedby filtration and dried under reduced pressure to obtainN-(3-piperidinyl)-1H-indazole-5-carboxamide (0.250 g, 96%).

Melting point: 265–266° C.

EXAMPLE 140 Synthesis ofN-(1-methylpiperidin-3-yl)-1H-indazole-5-carboxamide

Acetic acid (0.12 ml, 2.1 mmol) was added to a suspension of theN-(3-piperidinyl)-1H-indazole-5-carboxamide (0.100 g, 0.409 mmol)obtained in Example 139 and paraformaldehyde (0.101 g, 3.34 mmol) inmethanol (3 ml), and the resulting mixture was stirred for 15 minutesand then ice-cooled. Sodium cyanoborohydride (0.128 g, 2.04 mmol) wasadded thereto and the resulting mixture was slowly warmed up to roomtemperature and stirred overnight. After a 1N-aqueous sodium hydroxidesolution was added thereto, the solvent was distilled off under reducedpressure and the residue was dried up and then purified by a silica gelchromatography (eluent: chloroform/methanol/30% aqueousammonia=100/10/1). Ethyl acetate was added thereto to precipitate asolid and the resulting suspension was stirred to wash the solid. Thesolid was collected by filtration and dried under reduced pressure toobtain N-(1-methylpiperidin-3-yl)-1H-indazole-5-carboxamide (0.0718 g,68%).

Melting point: 228–229° C.

The following compounds of Example 141 to Example 146 were synthesizedby carrying out reaction according to the method described in Example99, except for using the N-(3-piperidinyl)-1H-indazole-5-carboxamideobtained in Example 139, as a starting material.

EXAMPLE 141 N-(1-butylpiperidin-3-yl)-1H-indazole-5-carboxamide

MS: m/z=301 (M+1)

EXAMPLE 142N-[1-(cyclohexylmethyl)piperidin-3-yl]-1H-indazole-5-carboxamide

MS: m/z=341 (M+1)

EXAMPLE 143 N-(1-isopropylpiperidin-3-yl)-1H-indazole-5-carboxamide

MS: m/z=287 (M+1)

EXAMPLE 144 N-(1-cyclobutylpiperidin-3-yl)-1H-indazole-5-carboxamide

MS: m/z=299 (M+1)

EXAMPLE 145 N-(1-cyclopentylpiperidin-3-yl)-1H-indazole-5-carboxamide

MS: m/z=313 (M+1)

EXAMPLE 146 N-(1-cyclohexylpiperidin-3-yl)-1H-indazole-5-carboxamide

MS: m/z=327 (M+1)

EXAMPLE 147 Synthesis ofN-(1-benzylazepan-3-yl)-1H-indazole-5-carboxamide (a) Synthesis of3-amino-2-azepanone

Hexamethyldisilazane (30 ml) and chloro-trimethylsilane (several drops)were added to a suspension of DL-lysine (3.0 g, 20.5 mmol) in xylene(270 ml) at room temperature, and the reaction was carried out at 140°C. for 48 hours. The reaction mixture was cooled and then poured intoethanol (600 ml), and the resulting mixture was concentrated. Theresulting residue was suspended in chloroform, followed by filtrationand concentration, whereby 3-amino-2-azepanone (1.59 g, 60%) wasobtained.

¹H-NMR (DMSO-d₆): 1.08–1.36 (2H, m), 1.51–1.84 (6H, m), 3.00–3.12 (2H,m), 3.95–3.96 (1H, m), 7.56 (1H, brs).

(b) Synthesis of 3-(tritylamino)-2-azepanone

Triethylamine (1.75 ml, 12.6 mmol) and triphenylmethyl chloride (3.50 g,12.6 mmol) were added to a solution of 3-amino-2-azepanone (1.46 g, 11.4mmol) in chloroform (44 ml) at room temperature and stirred overnight atroom temperature. The reaction mixture was poured into water and thenextracted with chloroform. The organic layer was washed with a saturatedaqueous sodium chloride solution and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/ethyl acetate) to obtain 3-(tritylamino)-2-azepanone(2.93 g, 69%).

¹H-NMR (DMSO-d₆): 0.98–1.36 (4H, m), 1.48–1.54 (2H, m), 2.63–2.81 (2H,m), 3.22 (1H, m), 3.95–3.96 (1H, m), 7.16–7.49 (15H, m), 7.51–7.52 (1H,m).

(c) Synthesis of 1-benzyl-3-(tritylamino)-2-azepanone

To a suspension of 3-(tritylamino)-2-azepanone (2.85 g, 7.69 mmol) intetrahydrofuran (30 ml) was added 60%-sodium hydride (462 mg, 11.6 mmol)at 0° C., and then stirred at room temperature for 30 minutes.Subsequently, a solution of benzyl bromide (1.0 ml, 8.41 mmol) intetrahydrofuran (5 ml) was added dropwise thereto at room temperatureover a period of 3 minutes, followed by adding theretotetra-n-butylammonium iodide (57 mg, 0.15 mmol), and the resultingmixture was stirred at room temperature for 6 hours. The reactionmixture was cooled on an ice-water bath and t-butanol (0.7 ml) and water(1 ml) were added thereto at 0° C. The resulting mixture was poured intowater and then extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous sodium chloride solution and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: n-hexane/chloroform) to obtain1-benzyl-3-(tritylamino)-2-azepanone (2.22 g, 63%).

¹H-NMR (DMSO-d₆): 1.05 (1H, m), 1.22–1.44 (4H, m), 1.59–1.65 (2H, m),2.85–3.02 (2H, m), 3.41–3.45 (1H, m), 3.97 (1H, d, J=5.9 Hz), 4.00 (1H,d, J=15.0 Hz), 4.60 (1H, d, J=14.7 Hz), 6.96–6.99 (2H, m), 7.18–7.41(18H, m).

(d) Synthesis of 1-benzyl-N-trityl-3-azepanamine

A solution of 1-benzyl-3-(tritylamino)-2-azepanone (425 mg, 0.922 mmol)in tetrahydrofuran (11 ml) was added dropwise to a suspension of lithiumaluminum hydride (140 mg, 3.69 mmol) in tetrahydrofuran (22 ml) at roomtemperature, and the resulting mixture was stirred for 30 minutes andthen refluxed for 3 hours. After the reaction mixture was cooled, water(0.14 ml), a 2N-aqueous sodium hydroxide solution (0.3 ml) and water(0.14 ml) were added thereto under ice-cooling. The resulting mixturewas filtered and the solvent of the filtrate was distilled off underreduced pressure. The resulting residue was purified by a silica gelcolumn chromatography (eluent: chloroform/methanol) to obtain1-benzyl-N-trityl-3-azepanamine (319 mg, 78%).

¹H-NMR (DMSO-d₆): 1.22–1.65 (7H, m), 2.08–2.23 (2H, m) 2.43–2.50 (1H,m), 2.59 (2H, brs), 3.17 (1H, d, J=13.6 Hz), 3.24 (1H, d, J=13.6 Hz),7.12–7.27 (14H, m), 7.44 (6H, m).

(e) Synthesis of 1-benzyl-3-azepanamine

Formic acid (0.25 ml, 6.63 mmol) was added dropwise to a solution of1-benzyl-N-trityl-3-azepanamine (300 mg, 0.672 mmol) in methylenechloride (7 ml) under ice-cooling and stirred under ice-cooling for 3.5hours. After the reaction mixture was concentrated, the residue wasdiluted with ether and washed with 1N-hydrochloric acid. Afterextraction, a 1N-aqueous sodium hydroxide solution was added to theaqueous layer under ice-cooling to make the aqueous layer basic,followed by extraction with chloroform. The organic layer was dried overmagnesium sulfate and then concentrated to obtain 1-benzyl-3-azepanamine(100 mg, 73%).

¹H-NMR (DMSO-d₆): 1.26–1.60 (5H, m), 1.70–1.74 (1H, m), 2.28 (1H, dd,J=8.1, 13.0 Hz), 2.68 (1H, dd, J=4.0, 13.0 Hz), 2.77–2.86 (1H, m), 3.25(2H, br), 3.57 (1H, d, J=15.2 Hz), 3.62 (1H, d, J=15.4 Hz), 7.18–7.31(5H, m).

(f) Synthesis of N-(1-benzylazepan-3-yl)-1H-indazole-5-carboxamide

N-(1-benzylazepan-3-yl)-1H-indazole-5-carboxamide was obtained bycarrying out reaction according to the method described in Example 45,except for using 1-benzyl-3-azepanamine.

MS: m/z=349 (M+1)

EXAMPLE 148 Synthesis of N-azepan-3-yl-1H-indazole-5-carboxamide

Ammonium formate (716 mg, 11.4 mmol) and 10% palladium carbon(containing 50% water, 100 mg) were added to a solution of theN-(1-benzylazepan-3-yl)-1H-indazole-5-carboxamide (494 mg, 1.42 mmol)obtained in Example 147 in ethanol (28 ml) at room temperature, and theresulting mixture was stirred with heating under reflux for 5 hours. Thereaction mixture was filtered to remove the catalyst and the solvent ofthe filtrate was distilled off under reduced pressure. The resultingresidue was purified by a silica gel column chromatography (eluent:ethyl acetate/methanol/aqueous ammonia=10/1/0.1) to obtainN-azepan-3-yl-1H-indazole-5-carboxamide (267 mg, 73%).

MS: m/z=259 (M+1)

The following compounds of Example 149 to Example 154 were synthesizedby carrying out reaction according to the method described in Example99, except for using the N-azepan-3-yl-1H-indazole-5-carboxamideobtained in Example 148, as a starting material.

EXAMPLE 149 N-(1-methylazepan-3-yl)-1H-indazole-5-carboxamide

MS: m/z=273 (M+1)

EXAMPLE 150 N-(1-butylazepan-3-yl)-1H-indazole-5-carboxamide

MS: m/z=315 (M+1)

EXAMPLE 151 N-(1-isopropylazepan-3-yl)-1H-indazole-5-carboxamide

MS: m/z=301 (M+1)

EXAMPLE 152 N-(1-cyclobutylazepan-3-yl)-1H-indazole-5-carboxamide

MS: m/z=313 (M+1)

EXAMPLE 153 N-(1-cyclopentylazepan-3-yl)-1H-indazole-5-carboxamide

MS: m/z=327 (M+1)

EXAMPLE 154N-(1-tetrahydro-2H-pyran-4-ylazepan-3-yl)-1H-indazole-5-carboxamide

MS: m/z=343 (M+1)

EXAMPLE 155 Synthesis ofN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-5-carboxamide (a)Synthesis of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime

A 50%-aqueous hydroxylamine solution (182 mg, 2.76 mmol) was added to asolution of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (538 mg, 2.50 mmol)in ethanol (5 ml) at room temperature and stirred at room temperaturefor 4 hours. The reaction mixture was concentrated and the resultingresidue was purified by a silica gel column chromatography (eluent:chloroform/methanol) to obtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-oneoxime (516 mg, 90%).

¹H-NMR (DMSO-d₆) δ; 1.49–1.69 (2H, m), 2.04–2.25 (4H, m), 2.59 (1H, dd,J=3.3, 14.9 Hz), 2.98 (1H, d, J=15.4 Hz), 3.35 (2H, m), 3.65 (2H, s),7.23–7.41 (6H, m).

(b) Synthesis of 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine

A suspension of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime (230 mg,0.999 mmol) in tetrahydrofuran (4 ml) was added dropwise to a suspensionof lithium aluminum hydride (152 mg, 4.01 mmol) in tetrahydrofuran (3ml) at room temperature, and the resulting mixture was refluxed for 8hours. The reaction mixture was cooled on an ice-water bath, and water(0.2 ml), a 2N-aqueous sodium hydroxide solution (0.4 ml) and water (0.2ml) were added thereto in that order and stirred. Subsequently, theresulting mixture was filtered and the solvent of the filtrate wasdistilled off to obtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine (246mg) containing a small amount of impurities.

(c) Synthesis ofN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-5-carboxamide

N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-5-carboxamide wasobtained by carrying out reaction according to the method described inExample 45, except for using 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine.

MS: m/z=361 (M+1)

The following compound of Example 156 was synthesized by carrying outreaction according to the method described in Example 148, except forusing theN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-5-carboxamideobtained in Example 155, as a starting material.

EXAMPLE 156 N-(8-azabicyclo[3,2,1]oct-3-yl)-1H-indazole-5-carboxamide

MS: m/z=271 (M+1)

The following compound of Example 157 was synthesized by carrying outreaction according to the method described in Example 45.

EXAMPLE 157 N-(1-azabicyclo[2,2,2]oct-3-yl)-1H-indazole-5-carboxamide

MS: m/z=271 (M+1)

EXAMPLE 158 Synthesis oftrans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexylcarbamate(a) Trans-tert-butyl 4-aminocyclohexylcarbamate

A solution of di-tert-butyldicarbonate (4.78 g, 21.9 mmol) in chloroform(75 ml) was added to a solution of trans-1,4-diaminocyclohexane (5.0 g,43.8 mmol) in chloroform (100 ml) at room temperature and stirred for1.5 hours. The reaction solution was concentrated, diluted withmethylene chloride, and then washed with a saturated aqueous sodiumhydrogencarbonate solution. The organic layer was dried over anhydrousmagnesium sulfate and distilled under reduced pressure to remove thesolvent. The resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol/aqueous ammonia=90/10/1) toobtain trans-tert-butyl 4-aminocyclohexylcarbamate (2.81 g, 60%).

(b) Synthesis oftrans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexylcarbamate

To a solution of the 1H-indazole-5-carboxylic acid (200 mg, 1.23 mmol)obtained in Reference Example 1 in N,N-dimethylformamide (15 ml) wereadded trans-tert-butyl 4-aminocyclohexylcarbamate (317 mg, 1.48 mmol),triethylamine (0.172 ml, 1.23 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (355mg, 1.85 mmol) and hydroxybenzotriazole (200 mg, 1.48 mmol), and theresulting mixture was stirred at room temperature for 1 hour. After thereaction solution was heated at 50° C. for 1 hour, water was addedthereto at 0° C. The resulting solid was filtered and then dried underreduced pressure to obtaintrans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexylcarbamate(435 mg, 98%).

¹H-NMR (DMSO-d₆) δ; 1.18–1.44 (6H, m), 1.36 (9H, s), 1.82 (4H, m), 7.54(1H, d, J=8.6 Hz), 7.81 (1H, d, J=8.6 Hz), 8.17 (1H, s), 8.19 (1H, d,J=7.6 Hz), 8.29 (1H, s).

EXAMPLE 159 Synthesis of N-(4-aminocyclohexyl)-1H-indazole-5-carboxamidetrifluoroacetate

Trifluoroacetic acid (6.0 ml) was added to thetrans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclo-hexylcarbamate(420 mg, 1.17 mmol) obtained in Example 158, and the resulting mixturewas stirred at room temperature for 1 hour. After the reaction solutionwas concentrated under reduced pressure, ethanol (10 ml) was added tothe concentration residue, followed by washing by repulping. The residuewashed was filtered and then dried under reduced pressure to obtainN-(4-aminocyclohexyl)-1H-indazole-5-carboxamide trifluoroacetate (363mg, 83%).

¹H-NMR (DMSO-d₆) δ; 1.44 (4H, m), 1.96 (4H, m), 3.00 (1H, m), 3.73 (1H,m), 7.56 (1H, d, J=8.9 Hz), 7.80 (2H, m), 8.19 (1H, s), 8.28 (1H, d,J=7.7 Hz), 8.30 (1H, s), 13.27 (1H, s).

EXAMPLE 160 Synthesis of N-(4-oxocyclohexyl)-1H-indazole-5-carboxamide(a) Synthesis of tert-butyl 4-hydroxycyclohexylcarbamate

An aqueous solution (52.5 ml) of sodium hydroxide (2.91 g, 72.8 mmol)was added to a t-butanol suspension (122.5 ml) oftrans-4-aminocyclohexanol (8.06 g, 70.0 mmol) at room temperature,followed by adding thereto di-t-butyl dicarbonate (15.9 g, 72.9 mmol),and the resulting mixture was stirred overnight at room temperature.Water was added to the reaction mixture, followed by extraction withn-hexane. The suspended organic layer was filtered and the precipitatewas dried to obtain tert-butyl 4-hydroxycyclohexylcarbamate (2.70 g) asa white solid. The aqueous layer was neutralized with 1N-hydrochloricacid and then extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous sodium chloride solution and then dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/ethyl acetate) to obtain tert-butyl4-hydroxycyclohexylcarbamate (11.3 g) (14.0 g in total, 93%).

¹H-NMR (DMSO-d₆): 1.06–1.20 (4H, m), 1.35 (9H, s), 1.69–1.76 (4H, m),3.12–3.31 (2H, m), 4.48 (1H, s), 6.64 (1H, d, J=7.5 Hz).

(b) Synthesis of Tert-butyl 4-oxocyclohexylcarbamate

A methylene chloride solution (6 ml) of dimethyl sulfoxide (2.0 ml, 28.2mmol) was added dropwise to a methylene chloride solution (30 ml) ofoxalyl chloride (1.7 ml, 19.5 mmol) at −60° C. over a period of 10minutes and stirred at −60° C. for another 10 minutes. Then, a methylenechloride solution (140 ml) of tert-butyl 4-hydroxycyclohexylcarbamate(2.56 g, 11.9 mmol) was added dropwise thereto over a period of 35minutes, and the resulting mixture was stirred at −60° C. for 40minutes. After triethylamine (8.4 ml, 60.3 mmol) was added thereto at−60° C., the resulting mixture was warmed up to room temperaturespontaneously. Water was added to the reaction mixture, followed byextraction with chloroform. The organic layer was washed with asaturated aqueous ammonium chloride solution and a saturated aqueoussodium chloride solution and then dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:chloroform/ethyl acetate) to obtain tert-butyl 4-oxocyclohexylcarbamate(2.23 g, 87%).

¹H-NMR (DMSO-d₆): 1.06–1.20 (4H, m), 1.35 (9H, s), 1.69–1.76 (4H, m),3.12–3.31 (2H, m), 4.48 (1H, s), 6.64 (1H, d, J=7.5 Hz)

(c) Synthesis of 4-aminocyclohexanone

Trifluoroacetic acid (4.3 ml, 55.8 mmol) was added to a solution oftert-butyl 4-oxocyclohexylcarbamate (1.00 g, 4.69 mmol) in methylenechloride (47 ml) at room temperature and stirred overnight at roomtemperature. Then, the solvent of the reaction solution was distilledoff under reduced pressure and the resulting residue was poured into a1N-aqueous sodium hydroxide solution and extracted with ethyl acetateand chloroform. The organic layer was washed with a saturated aqueoussodium chloride solution and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtain4-aminocyclohexanone (378 mg) containing a small amount of impurities.

(d) Synthesis of N-(4-oxocyclohexyl)-1H-indazole-5-carboxamide

N-(4-oxocyclohexyl)-1H-indazole-5-carboxamide was obtained by carryingout reaction according to the method described in Example 45, except forusing 4-aminocyclohexanone.

MS: m/z=258 (M+1)

EXAMPLE 161 Synthesis ofN-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide

Acetic acid (0.096 ml) was added to a solution of theN-(4-oxocyclohexyl)-1H-indazole-5-carboxamide (40.0 mg, 0.155 mmol)obtained in Example 160 in methanol (1.2 ml), and the resulting solutionwas maintained at room temperature for 30 minutes. To this solution wasadded a 40% aqueous methylamine solution (60.0 mg, 0.777 mmol), and theresulting mixture was maintained at room temperature for another 2hours. Then, a solution of sodium cyanotrihydroborate (48.7 mg, 0.777mmol) in methanol (0.6 ml) was added dropwise thereto, and the resultingmixture was stirred for 22 hours while being maintained at roomtemperature. A 1N aqueous sodium hydroxide solution (0.8 ml) was addedto the reaction solution, and the resulting mixture was stirred whilebeing maintained at room temperature, and was then concentrated todryness. The resulting crude product residue was purified by a silicagel column chromatography (eluent: chloroform/methanol/aqueousammonia=10/1/0.1) to obtainN-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomerhaving a lower polarity) (12.2 mg, 29%) andN-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomerhaving a higher polarity) (28.3 mg, 67%).

MS: m/z=273 (M+1) for both isomers.

The following compounds of Example 162 to Example 170 were synthesizedby carrying out reaction according to the method described in Example 9,except for using thetrans-N-(4-aminocyclohexyl)-1H-indazole-5-carboxamide trifluoroacetateobtained in Example 159, as a starting material.

EXAMPLE 162trans-N-[4-(dimethylamino)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=287 (M+1)

EXAMPLE 163 trans-N-[4-(butylamino)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=315 (M+1)

EXAMPLE 164trans-N-[4-(isopropylamino)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=301 (M+1)

EXAMPLE 165trans-N-[4-(cyclobutylamino)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=313 (M+1)

EXAMPLE 166trans-N-[4-(cyclopentylamino)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=327 (M+1)

EXAMPLE 167trans-N-[4-(cyclohexylamino)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=341 (M+1)

EXAMPLE 168trans-N-[4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=343 (M+1)

EXAMPLE 169trans-N-(4-{[2-(benzyloxy)ethyl]amino}cyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=393 (M+1)

EXAMPLE 170trans-N-(4-piperidin-1-ylcyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=327 (M+1)

The following compounds of Examples 171 and 172 were synthesized bycarrying out reaction according to the method described in Example 161.

EXAMPLE 171 N-(4-azetidin-1-ylcyclohexyl)-1H-indazole-5-carboxamide

(Two Isomers Different in Polarity)

MS: m/z=299 (M+1) for both isomers.

EXAMPLE 172 N-(4-pyrrolidin-1-ylcyclohexyl)-1H-indazole-5-carboxamide

(Two Isomers Different in Polarity)

MS: m/z=313 (M+1) for both isomers.

The following compound of Example 173 was synthesized by carrying outreaction according to the method described in Example 138, except forusing 4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acidas a starting material.

EXAMPLE 173 trans-Benzyl{4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexyl}methylcarbamate

¹H-NMR (DMSO-d₆) δ; 0.92–1.05 (2H, m), 1.25–1.43 (3H, m), 1.70–1.78 (2H,m), 1.82–1.91 (2H, m), 2.88 (2H, d, J=6.3 Hz), 3.68–3.80 (1H, m), 5.01(2H, s), 7.28–7.40 (6H, m), 7.54 (1H, d, J=8.6 Hz), 7.84 (1H, dd, J=1.5,8.6 Hz), 8.18 (1H, d, J=7.4 Hz), 8.19 (1H, br), 8.31 (1H, s), 13.24 (1H,br)

The following compound of Example 174 was synthesized by carrying outreaction according to the method described in Example 139, except forusing the trans-benzyl{4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexyl}methylcarbamate obtainedin Example 173, as a starting material.

EXAMPLE 174trans-N-[4-(aminomethy)]cyclohexyl]-1H-indazole-5-carboxamide

Melting point: 259–261° C.

The following compounds of Example 175 to Example 183 were synthesizedby carrying out reaction according to the method described in Example99, except for using thetrans-N-[4-(aminomethy)cyclohexyl]-1H-indazole-5-carboxamide obtained inExample 174, as a starting material.

EXAMPLE 175trans-N-{4-[(dimethylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=301 (M+1)

EXAMPLE 176trans-N-{4-[(butylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=329 (M+1)

EXAMPLE 177trans-N-{4-[(isopropylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=315 (M+1)

EXAMPLE 178trans-N-{4-[(cyclobutylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=327 (M+1)

EXAMPLE 179trans-N-{4-[(dicyclobutylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=381 (M+1)

EXAMPLE 180trans-N-{4-[(cyclopentylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=341 (M+1)

EXAMPLE 181trans-N-{4-[(cyclohexylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=355 (M+1)

EXAMPLE 182trans-N-{4-[(tetrahydro-2H-pyran-4-ylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

MS: m/z=357 (M+1)

EXAMPLE 183trans-N-[4-(piperidin-1-ylmethyl)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=341 (M+1)

The following compounds of Example 184 to Example 186 were synthesizedby carrying out reaction according to the method described in Example45.

EXAMPLE 184 trans-N-(4-hydroxycyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=260 (M+1)

EXAMPLE 185 N-(4-methylcyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=258 (M+1)

EXAMPLE 186 Methyl4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate

MS: m/z=302 (M+1)

EXAMPLE 187 Synthesis ofN-(4-hydroxymethylcyclohexyl)-1H-indazole-5-carboxamide

Lithium borohydride (10.0 mg, 0.459 mmol) was added to a solution of themethyl 4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate (30.0mg, 0.0951 mmol) obtained in Example 186 in tetrahydrofuran (3.0 ml) atroom temperature, and the resulting mixture was stirred for 2 hours withheating under reflux while maintaining the temperature. A 1N aqueoussodium hydroxide solution (0.8 ml) was added to the reaction solution,and the resulting mixture was stirred while being maintained at roomtemperature, and then was concentrated to dryness. The resulting crudeproduct residue was stirred in methanol (3.0 ml) for another 1 hour withheating under reflux while maintaining the temperature. The resultingmixture was concentrated to dryness and purified by a silica gel columnchromatography (eluent: chloroform/methanol=20/1) to obtainN-(4-hydroxymethylcyclohexyl)-1H-indazole-5-carboxamide (23.5 mg, 91%).

MS: m/z=274 (M+1)

EXAMPLE 188 Synthesis oftert-butyl-3-[(1H-indazol-5-ylcarbonyl)amino]cyclohexyl carbamate (a)Synthesis of tert-butyl 3-aminocyclohexanecarbamate

A solution of di-tert-butyl dicarbonate (14.3 mg, 65.5 mmol) inchloroform (210 ml) was added dropwise to a solution of1,3-diaminocyclohexane (15.0 g, 131 mmol) in chloroform (300 ml), andthe resulting mixture was stirred overnight at room temperature. Aftercompletion of the reaction, the precipitate was removed. The solvent wasdistilled off from the filtrate under reduced pressure, and the residuewas purified by a silica gel chromatography (eluent:chloroform/methanol) to obtain tert-butyl 3-aminocyclohexanecarbamate(13.0 g, yield 92%).

(b) Synthesis of tert-butyl-3-[(1H-indazol-5-ylcarbonyl)amino]cyclohexylcarbamate

The title compound was synthesized by carrying out reaction according tothe method described in Example 138, (e), except for using tert-butyl3-aminocyclohexanecarbamate as a starting material.

¹H-NMR (DMSO-d₆) δ; 1.10 (4H, m), 1.72 (4H, m), 1.94 (1H, m), 3.79 (1H,m), 7.54 (1H, d), 7.83 (1H, d, J=7.1 Hz), 8.17 (1H, s), 8.25 (1H, d,J=7.9 Hz), 8.31 (1H, s), 13.23 (1H, s).

EXAMPLE 189 Synthesis of N-(3-aminocyclohexyl)-1H-indazole-5-carboxamide

The tert-butyl-3-[(1H-indazol-5-ylcarbonyl)amino]cyclohexyl carbamate(3.0 g, 8.3 mmol) obtained in Example 188 was suspended indichloromethane (32 ml), followed by adding dropwise theretotrifluoroacetic acid (30 ml), and the resulting mixture was stirredovernight at room temperature. The solvent was distilled off underreduced pressure and the trifluoroacetic acid was removed as anazeotrope with toluene and ethanol as much as possible. Theconcentration residue was dissolved in water (10 ml), followed by addingthereto a saturated aqueous sodium hydrogencarbonate solution (50 ml),and the resulting mixture was stirred at room temperature for 2 hours.Thereafter, the precipitate formed was collected by filtration. Theprecipitate on a filter was washed with water and dried under reducedpressure to obtain N-(3-aminocyclohexyl)-1H-indazole-5-carboxamide (2.2g, yield 99%).

¹H-NMR (DMSO-d₆) δ; 1.14 (4H, m), 1.76 (3H, m), 1.96 (1H, m), 2.72 (1H,m), 3.28 (1H, m), 3.80 (1H, m), 6.72 (1H, d, J=8.3 Hz), 7.54 (1H, d,J=8.8 Hz), 7.83 (1H, dd, J=1.5, 8.8 Hz), 8.25 (1H, d, J=7.9 Hz), 8.31(1H, s).

The following compounds of Examples 190 to 193 were synthesized bycarrying out reaction according to the method described in Example 140,except for using theN-[3-(aminomethyl)]cyclohexyl]-1H-indazole-5-carboxamide obtained inExample 189, as a starting material.

EXAMPLE 190 N-[3-(dimethylamino)]cyclohexyl]-1H-indazole-5-carboxamide

Melting point: 225–226° C.

EXAMPLE 191 N-[3-(isopropylamino)]cyclohexyl]-1H-indazole-5-carboxamide

Melting point: 222–223° C.

EXAMPLE 192 N-[3-(butylamino)]cyclohexyl]-1H-indazole-5-carboxamide

Melting point: 216–218° C.

EXAMPLE 193 N-[3-(cyclobutylamino)]cyclohexyl]-1H-indazole-5-carboxamide

Melting point: 247–249° C.

The following compound of Example 194 was synthesized by carrying outreaction according to the method described in Example 45.

EXAMPLE 194 Methyl3-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate

MS: m/z=302 (M+1)

The following compound of Example 195 was synthesized by carrying outreaction according to the method described in Example 187, except forusing the methyl3-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate obtained inExample 194, as a starting material.

EXAMPLE 195 N-[3-(hydroxymethyl)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=274 (M+1)

EXAMPLE 196 Synthesis ofN-{3-[(dibenzylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide (a)Synthesis of 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid

A solution of 3-aminocyclohexanecarboxylic acid (1.005 g, 7.02 mmol) ina mixture of a 2N-aqueous sodium hydroxide solution (14 ml, 28 mmol) and1,4-dioxane (15 ml) was cooled on a water bath, and di-tert-butyldicarbonate (3.25 ml, 14.1 mmol) was added thereto and stirredovernight. The resulting solution was diluted with water and washed withdiethyl ether, and the aqueous layer was adjusted to pH 6 to 7 with1N-hydrochloric acid and then to pH 2 to 3 with a 5%-aqueous potassiumhydrogensulfate solution. The aqueous layer was extracted three timeswith ethyl acetate, and the extract solution was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtain3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (1.587 g, 93%).

(b) Synthesis of tert-butyl 3-[(dibenzylamino)carbonyl]cyclohexanecarbamate

A solution of dibenzylamine (0.448 g, 2.27 mmol) in dichloromethane (3ml), 1-hydroxybenztriazole (0.337 g, 2.49 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.477g, 2.49 mmol) were added to a solution of3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (0.502 g, 2.06mmol) in dichloromethane (7 ml) and stirred overnight. The resultingsolution was diluted with ethyl acetate and washed with a 5%-aqueouspotassium hydrogensulfate solution (twice), a saturated aqueous sodiumhydrogencarbonate solution (twice) and a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure and the residue waspurified by a silica gel chromatography (eluent: chloroform/ethylacetate=20/1) to obtain tert-butyl3-[(dibenzylamino)carbonyl]cyclohexanecarbamate (0.796 g, 91%).

(c) Synthesis of 3-amino-N,N-dibenzylcyclohexane-carboxamidemonohydrochloride

A 4N-hydrochloric acid/1,4-dioxane solution (4.5 ml) was added to asolution of tert-butyl 3-[(dibenzylamino)carbonyl]cyclohexanecarbamate(0.749 g, 1.773 mmol) in tetrahydrofuran (4.5 ml) and stirred overnight.The solvent was distilled off under reduced pressure, followed byreplacement with toluene (twice), whereby3-amino-N,N-dibenzylcyclohexanecarboxamide monohydrochloride (0.848g, >99%) was obtained.

(d) Synthesis of 3-[(dibenzylamino)methyl]cyclohexanamine

A solution of 3-amino-N,N-dibenzylcyclohexane-carboxamidemonohydrochloride (0.848 g) in tetrahydrofuran (5 ml) was added dropwiseto a suspension of lithium aluminum hydride (0.337 g, 8.89 mmol) intetrahydrofuran (5 ml), and the resulting mixture was stirred withheating under reflux for 3 hours. The resulting solution was cooled onan ice bath, followed by adding dropwise thereto water (0.33 ml), a2N-aqueous sodium hydroxide solution (0.66 ml) and water (1.0 ml) inthat order. Thereafter, the insoluble material was removed by filtrationusing Celite. The solvent was distilled off from the filtrate underreduced pressure, followed by replacement with ethanol (once) andtoluene (twice). Then, the residue was dried under reduced pressure toobtain 3-[(dibenzylamino)methyl]cyclohexanamine (0.550 g, 99%).

(e) Synthesis ofN-{3-[(dibenzylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide

The 1H-indazole-5-carboxylic acid (0.285 g, 1.75 mmol) obtained inReference Example 1, 1-hydroxybenztriazole (0.285 g, 2.11 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.409g, 2.13 mmol) were added to a solution of3-[(dibenzylamino)methyl]cyclohexanamine (0.542 g, 1.76 mmol) inN,N-dimethylformamide (5 ml) and stirred overnight. A 1N-aqueous sodiumhydroxide solution was added thereto, followed by extraction with ethylacetate (three times), and the extract solution was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the residue was purified by a silica gel chromatography (eluent:chloroform/methanol=30/1) to obtainN-{3-[(dibenzylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamide (0.605g, 76%).

¹H-NMR (DMSO-d₆) δ; 0.52–0.63 (1H, m), 0.75–0.86 (1H, m), 1.13–1.37 (2H,m), 1.69–1.88 (4H, m), 1.93–2.03 (1H, m), 2.19 (2H, d, J=7.3 Hz), 3.49(4H, s), 3.75–3.87 (1H, m), 7.20–7.26 (2H, m), 7.30–7.37 (8H, m), 7.55(1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.6, 8.7), 8.17 (1H, d, J=7.9 Hz),8.19 (1H, br), 8.31 (1H, s), 13.25 (1H, br).

The following compound of Example 197 was synthesized by carrying outreaction according to the method described in Example 139, except forusing theN-{3-[(dibenzylamino)methyl]cyclohexyl}-1H-indazole-5-carboxamideobtained in Example 196, as a starting material.

EXAMPLE 197 N-[3-(aminomethyl)]cyclohexyl]-1H-indazole-5-carboxamide

Melting point: 230–231° C.

The following compounds of Example 198 to Example 201 were synthesizedby carrying out reaction according to the method described in Example45.

EXAMPLE 198 cis-N-(2-hydroxycyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=260 (M+1)

EXAMPLE 199 N-(2-hydroxycyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=260 (M+1)

EXAMPLE 200 N-(2-methylcyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=258 (M+1)

EXAMPLE 201 cis-ethyl2-{(1H-indazol-5-ylcarbonyl)amino}cyclohexanecarboxylate

MS: m/z=316 (M+1)

The following compound of Example 202 was synthesized by carrying outreaction according to the method described in Example 187, except forusing the cis-ethyl2-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate obtained inExample 201, as a starting material.

EXAMPLE 202cis-N-[2-(hydroxymethyl)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=274 (M+1)

The following compound of Example 203 was synthesized by carrying outreaction according to the method described in Example 45.

EXAMPLE 203 trans-ethyl2-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate

MS: m/z=316 (M+1)

The following compound of Example 204 was synthesized by carrying outreaction according to the method described in Example 187, except forusing the trans-ethyl2-{(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate obtained inExample 203, as a starting material.

EXAMPLE 204trans-N-[2-(hydroxymethyl)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=274 (M+1)

The following compound of Example 205 was synthesized by carrying outreaction according to the method described in Example 45.

EXAMPLE 205 Methyl1-{(1H-indazol-5-ylcarbonyl)amino}cyclo-hexanecarboxylate

MS: m/z=302 (M+1)

The following compound of Example 206 was synthesized by carrying outreaction according to the method described in Example 187, except forusing the methyl1-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate obtained inExample 205, as a starting material.

EXAMPLE 206 N-[1-(hydroxymethyl)cyclohexyl]-1H-indazole-5-carboxamide

MS: m/z=274 (M+1)

EXAMPLE 207 Synthesis ofN-(1-benzyl-5-oxopyrrolidin-3-yl)-1H-indazole-5-carboxamide (a)Synthesis of 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid

Methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate (2.00 g, 8.57 mmol) wasdissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (10ml), followed by adding thereto a 2N aqueous lithium hydroxide solution(8.6 ml, 17.2 mmol), and the resulting mixture was heated under refluxfor 20 minutes. After completion of the reaction, the reaction solutionwas ice-cooled, made into an acidic solution with an aqueous potassiumhydrogensulfate solution, and then extracted with ethyl acetate. Theethyl acetate layer was concentrated, washed by repulping (ethylacetate/hexane), and then dried to obtain1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid (1.83 g, 97%).

¹H-NMR (DMSO-d₆) δ; 2.56 (2H, m), 3.80 (1H, m), 3.15 (2H, m), 3.25 (2H,m), 4.36 (2H, q, J=8.6 Hz), 7.27 (5H, m), 12.61 (1H, s)

(b) Synthesis of tert-butyl 1-benzyl-5-oxo-3-pyrrolidinylcarbamate

In tert-butyl alcohol (6 ml) was dissolved1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid (1.00 g, 4.56 mmol), andtriethylamine (0.76 ml, 5.5 mmol) was added thereto. Then, a solution ofdiphenylphosphoryl azide (1.38 g, 5.02 mmol) in tert-butyl alcohol (4ml) was added thereto, and the resulting mixture was refluxed for 2hours. After completion of the reaction, the reaction solution wasconcentrated and the tert-butyl alcohol was removed as an azeotrope withtoluene as much as possible. The residue was purified by a silica gelchromatography (eluent: ethyl acetate/hexane) to obtain tert-butyl1-benzyl-5-oxo-3-pyrrolidinylcarbamate (480 mg, 51%).

¹H-NMR (DMSO-d₆) δ; 1.34 (9H, s), 2.23 (1H, dd, J=5.7, 16.8 Hz), 2.61(1H, dd, J=8.6, 16.8 Hz), 3.01 (1H, dd, J=5.7, 9.9 Hz), 3.43 (1H, dd,J=8.6, 9.9 Hz), 4.03 (1H, m), 4.36 (2H, s), 7.30 (6H, m).

(c) Synthesis of 4-amino-1-benzyl-2-pyrrolidinone hydrochloride

In tetrahydrofuran (6 ml) was dissolved tert-butyl1-benzyl-5-oxo-3-pyrrolidinylcarbamate (480 mg, 1.65 mmol), followed byadding thereto 4N-hydrogen chloride/dioxane (6.0 ml, 24 mmol), and theresulting mixture was stirred overnight at room temperature. Aftercompletion of the reaction, diethyl ether (35 ml) was added to thereaction solution, and the resulting mixture was stirred at roomtemperature for 30 minutes and the precipitate was collected byfiltration. The precipitate was washed with diethyl ether and dried toobtain 4-amino-1-benzyl-2-pyrrolidinone hydrochloride (380 mg, 99%).

¹H-NMR (DMSO-d₆) δ; 2.23 (1H, dd, J=4.0, 17.2 Hz), 2.76 (1H, dd, J=8.6,17.2 Hz), 3.22 (1H, dd, J=4.0, 10.8 Hz), 3.53 (1H, dd, J=7.7, 10.8 Hz),3.89 (1H, bs), 4.30 (1H, d, J=15.0 Hz), 4.45 (1H, d, J=15.0 Hz), 7.30(5H, m), 8.32 (2H, bs).

(d) Synthesis ofN-(1-benzyl-5-oxo-3-pyrrolidinyl)-1H-indazole-5-carboxamide

N-(1-benzyl-5-oxo-3-pyrrolidinyl)-1H-indazole-5-carboxamide was obtainedby carrying out reaction according to the method described in Example45, except for using 4-amino-1-benzyl-2-pyrrolidinone hydrochloride.

¹H-NMR (DMSO-d₆) δ; 2.74 (1H, dd, J=8.6, 16.8 Hz), 3.17 (1H, dd, J=5.7,10.2 Hz), 3.53 (1H, dd, J=7.3, 10.5 Hz), 3.59 (1H, bs), 4.36 (1H, d,J=15.0 Hz), 4.53 (1H, d, J=15.0 Hz), 4.55 (1H, m), 7.28 (5H, m), 7.55(1H, d, J=8.7 Hz), 7.82 (1H, dd, J=1.5, 8.7 Hz), 8.20 (1H, s), 8.32 (1H,s), 8.74 (1H, d, J=6.6 Hz), 13.26 (1H, s).

The following compounds of Example 208 to Example 233 were synthesizedby carrying out reaction according to the method described in Example45.

EXAMPLE 208 N-(2-oxoazepan-3-yl)-1H-indazole-5-carboxamide

MS: m/z=273 (M+1)

EXAMPLE 209 N-cyclopropyl-1H-indazole-5-carboxamide

MS: m/z=202 (M+1)

EXAMPLE 210 N-cyclobutyl-1H-indazole-5-carboxamide

MS: m/z=216 (M+1)

EXAMPLE 211 N-cyclopentyl-1H-indazole-5-carboxamide

MS: m/z=230 (M+1)

EXAMPLE 212 N-cyclohexyl-1H-indazole-5-carboxamide

¹H-NMR (DMSO-d₆) δ; 1.14–1.34 (5H, m), 1.59–1.81 (5H, m), 3.77 (1H, m),7.53 (1H, d, J=8.8 Hz), 7.83 (1H, dd, J=1.5, 8.8 Hz), 8.16–8.18 (2H, m),8.31 (1H, s), 13.23 (1H, brs).

EXAMPLE 213 N-cycloheptyl-1H-indazole-5-carboxamide

MS: m/z=258 (M+1)

EXAMPLE 214 N-cyclooctyl-1H-indazole-5-carboxamide

MS: m/z=272 (M+1)

EXAMPLE 215 N-(1-adamantyl)-1H-indazole-5-carboxamide

MS: m/z=296 (M+1)

EXAMPLE 216 N-phenyl-1H-indazole-5-carboxamide

¹H-NMR (DMSO-d₆) δ; 7.08 (1H, t, J=7.3 Hz), 7.35 (2H, t, J=7.5 Hz), 7.63(1H, d, J=8.8 Hz), 7.79 (2H, d, J=7.5 Hz), 7.94 (1H, d, J=8.8 Hz), 8.26(1H, s), 8.47 (1H, s), 10.26 (1H, s), 13.34 (1H, brs).

EXAMPLE 217 N-(2-methylphenyl)-1H-indazole-5-carboxamide

MS: m/z=252 (M+1)

EXAMPLE 218 N-(3-methylphenyl)-1H-indazole-5-carboxamide

MS: m/z=252 (M+1)

EXAMPLE 219 N-(4-methylphenyl)-1H-indazole-5-carboxamide

MS: m/z=252 (M+1)

EXAMPLE 220 N-(1H-imidazol-2-yl)-1H-indazole-5-carboxamide

MS: m/z=228 (M+1)

EXAMPLE 221 N-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indazole-5-carboxamide

MS: m/z=247 (M+1)

EXAMPLE 222 N-benzyl-1H-indazole-5-carboxamide

MS: m/z=252 (M+1)

EXAMPLE 223 N-[2-(trifluoromethyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z=320 (M+1)

EXAMPLE 224 N-[3-(trifluoromethyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z=320 (M+1)

EXAMPLE 225 N-[4-(trifluoromethyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z=320 (M+1)

EXAMPLE 226 N-[2-(trifluoromethoxy)benzyl]-1H-indazole-5-carboxamide

MS: m/z=336 (M+1)

EXAMPLE 227 N-[3-(trifluoromethoxy)benzyl]-1H-indazole-5-carboxamide

MS: m/z=336 (M+1)

EXAMPLE 228 N-[4-(trifluoromethoxy)benzyl]-1H-indazole-5-carboxamide

MS: m/z=336 (M+1)

EXAMPLE 229 N-[4-(dimethylamino)benzyl]-1H-indazole-5-carboxamide

MS: m/z=295 (M+1)

EXAMPLE 230 N-[4-(aminosulfonyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z=331 (M+1)

EXAMPLE 231 N-[4-(methylsulfonyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z 330 (M+1)

EXAMPLE 232 N-(4-nitrobenzyl)-1H-indazole-5-carboxamide

MS: m/z=297 (M+1)

EXAMPLE 233 Methyl 4-{[(1H-indazol-5-ylcarbonyl)amino]-methyl}benzoate

MS: m/z=310 (M+1)

The following compound of Example 234 was synthesized by carrying outreaction according to the method described in Example 187, except forusing the methyl 4-{[(1H-indazol-5-ylcarbonyl)amino]methyl}benzoateobtained in Example 233, as a starting material.

EXAMPLE 234 N-[4-(hydroxymethyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z=282 (M+1)

The following compounds of Example 235 to Example 249 were synthesizedby carrying out reaction according to the method described in Example45.

EXAMPLE 235 N-(4-tert-butylbenzyl)-1H-indazole-5-carboxamide

MS: m/z=308 (M+1)

EXAMPLE 236 N-(2,3-dimethoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=312 (M+1)

EXAMPLE 237 N-(2,4-dimethoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=312 (M+1)

EXAMPLE 238 N-(2,5-dimethoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=312 (M+1)

EXAMPLE 239 N-(2,6-dimethoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=312 (M+1)

EXAMPLE 240 N-(3,4-dimethoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=312 (M+1)

EXAMPLE 241 N-(3,5-dimethoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=312 (M+1)

EXAMPLE 242 N-(2,3-difluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=288 (M+1)

EXAMPLE 243 N-(2,4-difluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=288 (M+1)

EXAMPLE 244 N-(2,5-difluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=288 (M+1)

EXAMPLE 245 N-(2,6-difluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=288 (M+1)

EXAMPLE 246 N-(3,4-difluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=288 (M+1)

EXAMPLE 247 N-(3,5-difluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=288 (M+1)

EXAMPLE 248N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-1H-indazole-5-carboxamide

MS: m/z=294 (M+1)

EXAMPLE 249 N-(2-phenylethyl)-1H-indazole-5-carboxamide

MS: m/z=266 (M+1)

EXAMPLE 250 Synthesis ofN-(piperidin-4-ylmethyl)-1H-indazole-5-carboxamide hydrochloride (a)Synthesis of tert-butyl4-{[(1H-indazol-5-ylcarbonyl)amino]methyl}piperidine-1-carboxylate

tert-Butyl4-{[(1H-indazol-5-ylcarbonyl)amino]methyl}piperidine-1-carboxylate wasobtained by carrying out reaction according to the method described inExample 45.

MS: m/z=359 (M+1)

(b) Synthesis of N-(piperidin-4-ylmethyl)-1H-indazole-5-carboxamidehydrochloride

A 4N-hydrogen chloride-1,4-dioxane solution (0.200 mg, 0.800 mmol) wasadded to a solution of tert-butyl4-{[(1H-indazol-5-ylcarbonyl)amino]methyl}piperidine-1-carboxylate (36.0mg, 0.100 mmol) in a mixture of 1,4-dioxane (0.4 ml) and acetic acid(0.7 ml) at room temperature, and the resulting mixture was stirred for3 hours while being maintained at room temperature. Toluene was added tothe reaction solution and the resulting mixture was stirred while beingmaintained at room temperature. Then, the resulting slurry was collectedby filtration and dried under reduced pressure, and the resulting crudeproduct residue was stirred in methanol (3.0 ml) for 1 hour with heatingunder reflux while maintaining the temperature. The resulting mixturewas concentrated to dryness to obtainN-(piperidin-4-ylmethyl)-1H-indazole-5-carboxamide hydrochloride (29.8mg, 100%).

MS: m/z=259 (M+1)

The following compounds of Example 251 to Example 270 were synthesizedby carrying out reaction according to the method described in Example45.

EXAMPLE 251 N-(tetrahydro-2H-pyran-4-ylmethyl)-1H-indazole-5-carboxamide

MS: m/z=260 (M+1)

EXAMPLE 252 1H-indazole-5-carboxamide

MS: m/z=162 (M+1)

EXAMPLE 253 N-methyl-1H-indazole-5-carboxamide

MS: m/z=176 (M+1)

EXAMPLE 254 N-propyl-1H-indazole-5-carboxamide

MS: m/z=204 (M+1)

EXAMPLE 255 N-(2,2,2-trifluoroethyl)-1H-indazole-5-carboxamide

MS: m/z=244 (M+1)

EXAMPLE 256 N-(3,3,3-trifluoropropyl)-1H-indazole-5-carboxamide

MS: m/z=258 (M+1)

EXAMPLE 257 N-isopropyl-1H-indazole-5-carboxamide

MS: m/z=204 (M+1)

EXAMPLE 258 N-(tert-butyl)-1H-indazole-5-carboxamide

MS: m/z=218 (M+1)

EXAMPLE 259 N-(2-hydroxy-1,1-dimethylethyl)-1H-indazole-5-carboxamide

MS: m/z=234 (M+1)

EXAMPLE 260 N-isopentyl-1H-indazole-5-carboxamide

¹H-NMR (CDCl₃) δ; 0.98 (6H, d, J=6.4 Hz), 1.51–1.58 (2H, m), 1.65–1.77(1H, m), 3.49–3.56 (2H, m), 6.11 (1H, brs), 7.53 (1H, d, J=8.8 Hz), 7.84(1H, d, J=8.8 Hz), 8.16 (1H, s), 8.21 (1H, s), 10.33 (1H, brs).

EXAMPLE 261 N-(2-methoxyethyl)-1H-indazole-5-carboxamide

MS: m/z=220 (M+1)

EXAMPLE 262 N-(3-methoxypropyl)-1H-indazole-5-carboxamide

MS: m/z=234 (M+1)

EXAMPLE 263 N-(2-hydroxyethyl)-1H-indazole-5-carboxamide

MS: m/z=206 (M+1)

EXAMPLE 264 N-[2-(dimethylamino)ethyl]-1H-indazole-5-carboxamide

MS: m/z=233 (M+1)

EXAMPLE 265 N-[3-(dimethylamino)propyl]-1H-indazole-5-carboxamide

MS: m/z=247 (M+1)

EXAMPLE 266N-[2-(dimethylamino)-1-methylethyl]-1H-indazole-5-carboxamide

MS: m/z=247 (M+1)

EXAMPLE 267 N-(2-pyrrolidin-1-ylethyl)-1H-indazole-5-carboxamide

MS: m/z=259 (M+1)

EXAMPLE 268 N-(2-piperidin-1-ylethyl)-1H-indazole-5-carboxamide

MS: m/z=273 (M+1)

EXAMPLE 269 N-(2-morpholin-4-ylethyl)-1H-indazole-5-carboxamide

MS: m/z=275 (M+1)

EXAMPLE 270N-[2-(4-benzylpiperazin-1-yl)ethyl]-1H-indazole-5-carboxamide

MS: m/z=364 (M+1)

The following compound of Example 271 was synthesized by carrying outreaction according to the method described in Example 148, except forusing the N-[2-(4-benzylpiperazin-1-yl)ethyl]-1H-indazole-5-carboxamideobtained in Example 270, as a starting material.

EXAMPLE 271 N-(2-piperazin-1-ylethyl)-1H-indazole-5-carboxamide

MS: m/z=274 (M+1)

The following compound of Example 272 was synthesized by carrying outreaction according to the method described in Example 45.

EXAMPLE 272N-[2-(1-benzylpiperidin-4-yl)ethyl]-1H-indazole-5-carboxamide

MS: m/z=363 (M+1)

The following compound of Example 273 was synthesized by carrying outreaction according to the method described in Example 148, except forusing the N-[2-(1-benzylpiperidin-4-yl)ethyl]-1H-indazole-5-carboxamideobtained in Example 272, as a starting material.

EXAMPLE 273 N-(2-piperidin-4-ylethyl)-1H-indazole-5-carboxamide

MS: m/z=273 (M+1)

The following compounds of Example 274 and Example 275 were synthesizedby carrying out reaction according to the method described in Example45.

EXAMPLE 274 N,N-dimethyl-1H-indazole-5-carboxamide

MS: m/z=190 (M+1)

EXAMPLE 275 N,N-dipropyl-1H-indazole-5-carboxamide

MS: m/z=246 (M+1)

EXAMPLE 276 Synthesis ofN-(1-phenylcyclohexyl)-1H-indazole-5-carboxamide

Oxalyl dichloride (38.7 μl, 0.444 mmol) and N,N-dimethylformamide (about1 μl) were added to a solution of the 1H-indazole-5-carboxylic acid(40.0 mg, 0.247 mmol) obtained in Reference Example 1 in dichloromethane(2.5 ml), and the resulting mixture was stirred at room temperature for0.5 hour and then was stirred with heating under reflux for 2 hourswhile maintaining the temperature. The reaction solution wasconcentrated to dryness and a solution of the resulting residue intetrahydrofuran (1.5 ml) was added dropwise to a solution of1-phenylcyclohexylamine (130 mg, 0.742 mmol) in tetrahydrofuran (2.0ml). The resulting mixture was stirred for 18 hours while beingmaintained at room temperature. A 5% aqueous sodium bicarbonate solutionwas added to the reaction solution and stirred, followed by extractionwith ethyl acetate. The organic phase was washed with a 5% aqueoussodium chloride solution and then dried over anhydrous sodium sulfate.The organic phase dried was concentrated under reduced pressure, and theresulting crude product was purified by a silica gel columnchromatography (eluent: chloroform/methanol=50/1 to 30/1) to obtainN-(1-phenylcyclohexyl)-1H-indazole-5-carboxamide (62 mg, 78%).

MS: m/z=320 (M+1)

The following compounds of Example 277 to Example 316 were synthesizedby carrying out reaction according to the method described in Example276.

EXAMPLE 277 1,3-bis[(1H-indazol-5-ylcarbonyl)amino]cyclohexane

MS: m/z=403 (M+1)

EXAMPLE 278 cis-N-(2-aminocyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=259 (M+1)

EXAMPLE 279 trans-N-(2-aminocyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=259 (M+1)

EXAMPLE 280 N-(1-ethynylcyclohexyl)-1H-indazole-5-carboxamide

MS: m/z=268 (M+1)

EXAMPLE 281 N-(2-methoxyphenyl)-1H-indazole-5-carboxamide

MS: m/z=268 (M+1)

EXAMPLE 282 N-(3-methoxyphenyl)-1H-indazole-5-carboxamide

MS: m/z=268 (M+1)

EXAMPLE 283 N-(4-methoxyphenyl)-1H-indazole-5-carboxamide

MS: m/z=268 (M+1)

EXAMPLE 284 N-[2-(aminocarbonyl)phenyl]-1H-indazole-5-carboxamide

MS: m/z=281 (M+1)

EXAMPLE 285 N-[3-(aminocarbonyl)phenyl]-1H-indazole-5-carboxamide

MS: m/z=281 (M+1)

EXAMPLE 286 N-(2-fluorophenyl)-1H-indazole-5-carboxamide

MS: m/z=256 (M+1)

EXAMPLE 287 N-(3-fluorophenyl)-1H-indazole-5-carboxamide

MS: m/z=256 (M+1)

EXAMPLE 288 N-(4-fluorophenyl)-1H-indazole-5-carboxamide

MS: m/z=256 (M+1)

EXAMPLE 289 N-pyridin-2-yl-1H-indazole-5-carboxamide

MS: m/z=239 (M+1)

EXAMPLE 290 N-pyridin-3-yl-1H-indazole-5-carboxamide

MS: m/z=239 (M+1)

EXAMPLE 291 N-pyridin-4-yl-1H-indazole-5-carboxamide

MS: m/z=239 (M+1)

EXAMPLE 292 N-pyrimidin-2-yl-1H-indazole-5-carboxamide

MS: m/z=240 (M+1)

EXAMPLE 293 N-(1H-1,2,4-triazol-3-yl)-1H-indazole-5-carboxamide

MS: m/z=229 (M+1)

EXAMPLE 294 N-(1H-tetrazol-5-yl)-1H-indazole-5-carboxamide

MS: m/z=230 (M+1)

EXAMPLE 295 N-(1,3-thiazol-2-yl)-1H-indazole-5-carboxamide

MS: m/z=245 (M+1)

EXAMPLE 296 N-(1,3,4-thiadiazol-2-yl)-1H-indazole-5-carboxamide

MS: m/z=246 (M+1)

EXAMPLE 297 N-(1H-benzimidazol-2-yl)-1H-indazole-5-carboxamide

MS: m/z=278 (M+1)

EXAMPLE 298 N-(1H-indazol-5-yl)-1H-indazole-5-carboxamide

MS: m/z=278 (M+1)

EXAMPLE 299 N-(2-methylbenzyl)-1H-indazole-5-carboxamide

MS: m/z=266 (M+1)

EXAMPLE 300 N-(3-methylbenzyl)-1H-indazole-5-carboxamide

MS: m/z=266 (M+1)

EXAMPLE 301 N-(4-methylbenzyl)-1H-indazole-5-carboxamide

MS: m/z=266 (M+1)

EXAMPLE 302 N-(2-methoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=282 (M+1)

EXAMPLE 303 N-(3-methoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=282 (M+1)

EXAMPLE 304 N-(4-methoxybenzyl)-1H-indazole-5-carboxamide

MS: m/z=282 (M+1)

EXAMPLE 305 N-(2-fluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=270 (M+1)

EXAMPLE 306 N-(3-fluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=270 (M+1)

EXAMPLE 307 N-(4-fluorobenzyl)-1H-indazole-5-carboxamide

MS: m/z=270 (M+1)

EXAMPLE 308 N-[4-(aminomethyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z=281 (M+1)

EXAMPLE 309 N-[3-(aminomethyl)benzyl]-1H-indazole-5-carboxamide

MS: m/z=281 (M+1)

EXAMPLE 310 1,4-bis[(1H-indazol-5-ylcarobonyl)aminomethyl]benzene

MS: m/z=425 (M+1)

EXAMPLE 311 1,3-bis[(1H-indazol-5-ylcarobonyl)aminomethyl]benzene

MS: m/z=425 (M+1)

EXAMPLE 312 N-(pyridin-2-ylmethyl)-1H-indazole-5-carboxamide

MS: m/z=253 (M+1)

EXAMPLE 313 N-(pyridin-3-ylmethyl)-1H-indazole-5-carboxamide

MS: m/z=253 (M+1)

EXAMPLE 314 N-(pyridin-4-ylmethyl)-1H-indazole-5-carboxamide

MS: m/z=253 (M+1)

EXAMPLE 315 N-(2-furylmethyl)-1H-indazole-5-carboxamide

MS: m/z=242 (M+1)

EXAMPLE 316 N-(thien-2-ylmethyl)-1H-indazole-5-carboxamide

MS: m/z=258 (M+1)

EXAMPLE 317 Synthesis of N-(1H-indazol-5-yl)piperidine-4-sulfonamide (a)Synthesis of benzyl 4-bromo-1-piperidinecarboxylate

To a solution of 4-bromopiperidine hydrobromide (3.0 g, 12.2 mmol) intetrahydrofuran (30 ml) were added1-{[(benzyloxy)carbonyl]oxy}-2,5-pyrrolidinedione (3.20 g, 12.9 mmol),N-methylmorpholine (1.62 ml, 14.7 mmol) and 4-N,N-dimethylaminopyridine(30 mg) at room temperature, and stirred at room temperature for 16hours. The reaction solution was poured into water and extracted withethyl acetate. The organic layer was washed with a 1N-aqueoushydrochloric acid solution, dried over anhydrous magnesium sulfate anddistilled under reduced pressure to remove the solvent, and theresulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate=1/1) to obtain benzyl4-bromo-1-piperidinecarboxylate (3.58 g, 98%).

(b) Synthesis of benzyl 4-(acetylthio)-1-piperidinecarboxylate

Potassium thiosulfate (1.47 g, 12.9 mmol) was added to a solution ofbenzyl 4-bromo-1-piperidinecarboxylate (3.5 g, 11.7 mmol) inN,N-dimethylformamide (25 ml) at room temperature and stirred at roomtemperature for 16 hours and then at 60° C. for 3 hours. The reactionsolution was poured into water and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and distilled underreduced pressure to remove the solvent, and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate=8/1) to obtain benzyl 4-(acetylthio)-1-piperidinecarboxylate(2.61 g, 76%).

(c) Synthesis of Benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate

A solution of benzyl 4-(acetylthio)-1-piperidinecarboxylate (1.45 g,4.94 mmol) in a mixture of methylene chloride (10 ml) and water (40 ml)was stirred at 0° C. for 4 hours while bubbling chlorine gastherethrough. After the organic layer was separated, the aqueous layerwas extracted with methylene chloride. The resulting organic layer wasdried over anhydrous magnesium sulfate and distilled under reducedpressure to remove the solvent, whereby benzyl4-(chlorosulfonyl)-1-piperidinecarboxylate (1.58 g, 100%) was obtained.

(d) Synthesis of 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole

To a solution of 5-nitroindazole (20.0 g, 123 mmol) in methylenechloride (400 ml) were added 3,4-dihydro-2H-pyran (16.8 ml, 184 mmol)and p-toluenesulfonic acid (4.22 g, 24.5 mmol) at room temperature, andstirred for 2 hours. After the reaction solution was concentrated, asaturated aqueous sodium hydrogencarbonate solution was added thereto,followed by extraction with chloroform. The organic layer was dried overanhydrous magnesium sulfate and distilled under reduced pressure toremove the solvent, and resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate=5/1) to obtain5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (26.6 g, 88%).

(e) Synthesis of 1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine

To a solution of 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (3.69 g,14.9 mmol) in a mixture of ethyl acetate (50 ml) and ethanol (50 ml) wasadded 10% Pd—C (300 mg), followed by catalytic reduction at ordinarytemperature and atmospheric pressure. After completion or the reaction,the catalyst was filtered off, and the filtrate was concentrated underreduced pressure. The resulting residue was suspended in ethyl acetate,and the solid precipitated was collected by filtration and dried underreduced pressure to obtain 1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine(1.79 g, 55%).

(f) Synthesis of benzyl4-{[(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]sulfonyl}-1-piperidinecarboxylate

Triethylamine (0.789 ml, 5.69 mmol) was added to a solution of1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (1.04 g, 4.79 mmol) andbenzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (1.5 g, 4.74 mmol) inmethylene chloride (50 ml) at 0° C. and stirred at 0° C. for 30 minutesand then at room temperature for 15 hours. The reaction solution waspoured into water and extracted with chloroform. The organic layer wasdried over anhydrous magnesium sulfate and distilled under reducedpressure to remove the solvent, and the resulting residue was purifiedby a silica gel column chromatography (eluent: chloroform/ethylacetate=3/1) to obtain benzyl4-{[(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]sulfonyl}-1-piperidinecarboxylate(1.32 g, 56%).

(g) Synthesis of Benzyl4-[(1H-indazol-5-ylamino)sulfonyl]-piperidine-1-carboxylate

Trifluoroacetic acid (5.0 ml) was added to a solution of benzyl4-{[(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]sulfonyl}-1-piperidinecarboxylate(500 mg, 1.00 mmol) in methylene chloride (50 ml) at room temperatureand stirred for 2 hours. After the reaction solution was concentrated, asaturated aqueous sodium hydrogencarbonate solution was added thereto,followed by extraction with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and distilled under reduced pressure toremove the solvent, and resulting residue was purified by a silica gelcolumn chromatography (eluent: chloroform/methanol=50/1) to obtainbenzyl 4-[(1H-indazol-5-ylamino)sulfonyl]piperidine-1-carboxylate (317mg, 76%).

(h) Synthesis of N-(1H-indazol-5-yl)piperidine-4-sulfonamide

Ammonium formate (250 mg) and 10%-Pd/C (50 mg) were added to a solutionof benzyl 4-[(1H-indazol-5-ylamino)sulfonyl]piperidine-1-carboxylate(250 mg, 0.603 mmol) in ethanol (15 ml) at room temperature, and theresulting mixture was refluxed for 1 hour. The reaction mixture wasfiltered by the use of Celite, and the filtrate was concentrated and theresulting residue was dissolved in a mixture of chloroform and methanol,followed by adding thereto diethyl ether. The solid precipitated wascollected by filtration and dried under reduced pressure to obtainN-(1H-indazol-5-yl)piperidine-4-sulfonamide (116 mg, 69%).

Melting point: 120–123° C.

EXAMPLE 318 Synthesis ofN-(1-benzylpiperidin-4-yl)-N-methyl-1H-indazole-5-carboxamide (a)Synthesis ofN-(1-benzyl-4-piperidinyl)-2,2,2-trifluoro-N-methylacetamide

N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoroacetamide (1.0 g, 3.49 mmol)was added to a suspension of 60%-sodium hydride (147 mg, 3.67 mmol) intetrahydrofuran (20 ml) at room temperature and stirred for 30 minutes.Then, methyl iodide (0.239 ml, 3.84 mmol) was added thereto and stirredfor 5 hours. The reaction solution was poured into water and extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent, andthe resulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol=100/1) to obtainN-(1-benzyl-4-piperidinyl)-2,2,2-trifluoro-N-methylacetamide (731 mg,70%).

(b) Synthesis of 1-benzyl-N-methylpiperidin-4-amine

Potassium carbonate (662 mg, 4.79 mmol) was added to a solution ofN-(1-benzyl-4-piperidinyl)-2,2,2-trifluoro-N-methylacetamide (720 mg,2.40 mmol) in a mixture of methanol (14 ml) and water (2 ml) at roomtemperature and stirred at 50° C. for 1.5 hours. After the reactionsolution was concentrated, a saturated aqueous sodium hydrogencarbonatesolution was added thereto, followed by extraction with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate and thendistilled under reduced pressure to remove the solvent, whereby1-benzyl-N-methylpiperidin-4-amine (629 mg, 100%) was obtained.

(c) Synthesis ofN-(1-benzylpiperidin-4-yl)-N-methyl-1H-indazole-5-carboxamide

To a solution of the 1H-indazole-5-carboxylic acid (281 mg, 1.73 mmol)obtained in Reference Example 1 in N,N-dimethylformamide (10 ml) wereadded 1-benzyl-N-methylpiperidin-4-amine (390 mg, 1.91 mmol),triethylamine (0.29 ml, 2.08 mmol),1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide monohydrochloride (499mg, 2.60 mmol) and hydroxybenzotriazole (281 mg, 2.08 mmol), and theresulting mixture was stirred overnight at room temperature. An aqueoussodium hydrogencarbonate solution was added to the reaction solution,followed by extraction with chloroform, and the organic layer was driedover anhydrous magnesium sulfate. The solvent was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: chloroform/ethylacetate→chloroform/methanol) to obtainN-(1-benzylpiperidin-4-yl)-N-methyl-1H-indazole-5-carboxamide (502 mg,83%).

¹H-NMR (DMSO-d₆) δ; 1.61 (2H, m), 1.78 (2H, m), 2.83 (5H, m), 3.39 (2H,s), 7.29 (6H, m), 7.57 (1H, d, J=8.5 Hz), 7.78 (1H, s), 8.12 (1H, s),13.22 (1H, s).

EXAMPLE 319 Synthesis ofN-methyl-N-piperidin-4-yl-1H-indazole-5-carboxamide

Ammonium formate (400 mg) and 10%-Pd/C (80 mg) were added to a solutionof the N-(1-benzylpiperidin-4-yl)-N-methyl-1H-indazole-5-carboxamide(435.1 mg, 1.25 mmol) obtained in Example 318 in ethanol (10 ml) at roomtemperature, and the resulting mixture was refluxed for 2 hours. Thereaction mixture was filtered by the use of Celite, and the filtrate wasconcentrated and the resulting residue was purified by a silica gelcolumn chromatography (eluent: chloroform/methanol (1%-aqueous ammonia))to obtain N-methyl-N-piperidin-4-yl-1H-indazole-5-carboxamide (247 mg,77%).

¹H-NMR (DMSO-d₆) δ; 1.61 (4H, m), 2.12 (2H, m), 2.92 (3H, s), 3.32 (2H,m), 3.32 (1H, m), 7.33 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=8.5 Hz), 7.78(1H, s), 8.13 (1H, s), 13.23 (1H, s).

EXAMPLE 320 Synthesis of 4-(piperidin-4-yloxy)-1H-indazole (a) Synthesisof 3-(acetylamino)-2-methylphenyl acetate

Under a nitrogen atmosphere, 10% Pd—C (1.0 g) was added to a solution of3-nitro-o-cresol (10.0 g, 65.3 mmol) in methanol (200 ml) at roomtemperature, and catalytic reduction was carried out at ordinarytemperature and atmospheric pressure. After completion of the reaction,the catalyst was filtered off and the filtrate was concentrated underreduced pressure. The resulting residue was dissolved in ethyl acetate,followed by adding thereto acetic anhydride (10.0 ml, 170 mmol) andpyridine (10.6 ml, 131 mmol), and the resulting mixture was refluxed for2 hours. After completion of the reaction, the reaction mixture wasconcentrated and hexane was added thereto. The resulting suspension wasfiltered and the precipitate was dried under reduced pressure to obtain3-(acetylamino)-2-methylphenyl acetate (12.7 g, 94%).

¹H-NMR (DMSO-d₆) δ; 1.96 (3H, s), 2.04 (3H, s), 2.29 (3H, s), 6.89 (1H,d, J=8.0 Hz), 7.16 (1H, dd, J=8.0, 8.0 Hz), 7.28 (1H, d, J=8.0 Hz), 9.39(1H, s).

(b) Synthesis of 1H-indazol-4-ol

Acetic anhydride (16.4 ml, 174 mmol), tetrabutylammonium bromide (933mg, 2.90 mmol), potassium acetate (11.4 g, 116 mmol) and isoamyl nitrite(11.7 ml, 86.9 mmol) were added to a solution of3-(acetylamino)-2-methylphenyl acetate (12.0 g, 57.9 mmol) in ethylacetate (120 ml) at room temperature, and the resulting mixture wasrefluxed for 7 hours. The reaction solution was poured into water andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and distilled under reduced pressure to remove thesolvent, and the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate=3/1). Subsequently, theresidue purified was dissolved in methanol (50 ml) and a 2N-aqueoussodium hydroxide solution (47.9 ml) was added thereto at roomtemperature and stirred for 1 hour. The methanol was distilled off underreduced pressure, and the resulting aqueous solution was adjusted to pH4 to 5 by dropwise addition of hydrochloric acid and then extracted withacetic acid. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent, andthe resulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate=2/1) to obtain 1H-indazol-4-ol (3.62 g,47%).

¹H-NMR (DMSO-d₆) δ; 6.36 (1H, d, J=7.9 Hz), 6.92 (1H, d, J=7.9 Hz), 7.19(1H, dd, J=7.9, 7.9 Hz), 8.01 (1H, s), 10.00 (1H, s), 12.85 (1H, brs).

(c) Synthesis of 4-(piperidin-4-yloxy)-1H-indazole

To a solution of 1H-indazol-4-ol (200 mg, 1.49 mmol) in tetrahydrofuran(10 ml) were added tert-butyl 4-hydroxypiperidine-1-carboxylate (300 mg,1.49 mmol), triphenylphosphine (430 mg, 1.64 mmol) and a 40%-dibenzylazodicarboxylate-dichloromethane solution (0.855 ml, 1.79 mmol) at 0° C.After 1 hour, the mixture thus obtained was warmed up to roomtemperature. After stirring overnight, the reaction solution wasconcentrated under reduced pressure, and the resulting residue wasdissolved in chloroform (30 ml) and washed with a 1M-aqueous sodiumhydroxide solution (20 ml). Extraction with chloroform (30 ml) wascarried out again and the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate). The mixture thusobtained was dissolved in methanol (2 ml) and 4N-hydrochloricacid-dioxane (2 ml) was added thereto at room temperature. After 2hours, the reaction solution was concentrated under reduced pressure,and the resulting residue was dissolved in methanol (5 ml) and the pHwas adjusted to 10 by dropwise addition of a 2M aqueous sodium hydroxidesolution. The resulting mixed solution was concentrated under reducedpressure, dried and then purified by a silica gel column chromatography(eluent: chloroform/methanol=10/1→chloroform/methanol/(1%-NH₃ aq)=10/1)to obtain 4-(piperidin-4-yloxy)-1H-indazole (103 mg, 32%).

Melting point: 162–165° C.

EXAMPLE 321 4-(Piperidin-3-yloxy)-1H-indazole (a) Synthesis ofTert-butyl 3-hydroxy-1-piperidinecarboxylate

A solution of di-tert-butyl dicarbonate (5.83 g, 26.7 mmol) indichloromethane (10 ml) was added to a solution of 3-hydroxypiperidine(3.0 g, 29.7 mmol) in dichloromethane (30 ml) at room temperature andstirred for 15 hours.

The reaction solution was concentrated, diluted with ethyl acetate, andthen washed with a saturated aqueous sodium hydrogencarbonate solution,a 0.5M-aqueous potassium hydrogensulfate solution, a saturated aqueoussodium hydrogencarbonate solution and then a saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent, andthe resulting residue was crystallized by the addition of hexane,filtered, and then dried to obtain tert-butyl3-hydroxy-1-piperidinecarboxylate (5.17 g, 87%).

¹H-NMR (DMSO-d₆) δ; 1.46 (9H, s, 1.99 (2H, m), 3.34–3.49 (4H, m), 4.45(1H, m).

(b) Synthesis of 4-(piperidin-3-yloxy)-1H-indazole

4-(Piperidin-3-yloxy)-1H-indazole was obtained by carrying out reactionaccording to the method described in Example 320, except for usingtert-butyl 3-hydroxy-1-piperidinecarboxylate.

¹H-NMR (DMSO-d₆) δ; 1.67 (1H, m), 1.94 (3H, m), 3.08 (2H, m), 3.27 (2H,m), 4.88 (1H, m), 6.64 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=8.0 Hz), 7.24(1H, dd, J=8.0, 8.0 Hz), 8.19 (1H, s), 8.73 (1H, brs.), 13.06 (1H, s).

EXAMPLE 322 Synthesis of 4-(azepan-4-yloxy)-1H-indazole (a) Synthesis of1-benzyl-4-azepanone

N-methyl-N-nitrosourethane (1.39 ml, 10.8 mmol) was added dropwise to asolution of 1-benzyl-4-piperidone (2.0 g, 10.6 mmol) in methanol (4 ml)at −15° C. over a period of 30 minutes while maintaining the temperatureat −5° C. or lower. During the addition, barium oxide (65 mg, 0.423mmol) was added thereto in small portions. The resulting mixture wasstirred overnight at −15° C. and then filtered, and the filtrate wasdistilled under reduced pressure to remove the solvent and diethyl etherwas added to the residue. The insoluble material was filtered off and asaturated aqueous sodium hydrogencarbonate solution was added to thefiltrate, followed by extraction with diethyl ether. The organic layerwas dried over anhydrous magnesium sulfate and distilled under reducedpressure to remove the solvent, and the resulting residue was purifiedby a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1)to obtain 1-benzyl-4-azepanone (662 mg, 31%).

¹H-NMR (CDCl₃) δ; 1.84 (2H, m), 2.54 (2H, m), 2.60 (2H, m), 2.73 (4H,s), 3.65 (2H, s), 7.25 (5H, m)

(b) Synthesis of 1-benzyl-4-azepanol

A solution of 1-benzyl-4-azepanone (610 mg, 3.00 mmol) in diethyl ether(8 ml) was added to a suspension of lithium aluminum hydride (57 mg,1.50 mmol) in diethyl ether (5 ml) at 0° C. and stirred for 1 hour.Water (0.057 ml), a 2N-aqueous sodium hydroxide solution (0.114 ml) andthen water (0.171 ml) were added to the reaction mixture, and theresulting mixture was dried over anhydrous magnesium sulfate anddistilled under reduced pressure to remove the solvent. The resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate 1/1, chloroform/methanol=30/1) to obtain1-benzyl-4-azepanol (516 mg, 84%).

¹H-NMR (CDCl₃) δ; 1.52–1.81 (4H, m), 1.87 (1H, m), 1.96 (1H, m), 2.44(1H, m), 2.53 (1H, m), 2.77 (1H, m), 2.87 (1H, m), 3.67 (2H, m), 4.08(1H, m), 7.28 (5H, m).

(c) Synthesis of Tert-butyl 4-hydroxyazepane-1-carboxylate

Ammonium formate (900 mg) and 10% Pd—C (200 mg) were added to a solutionof 1-benzyl-4-azepanol (450 mg, 2.19 mmol) in ethanol (10 ml), and theresulting mixture was refluxed for 1 hour. The reaction mixture wasfiltered by the use of Celite and the filtrate was concentrated. To asolution of the resulting residue in dichloromethane (10 ml) was addeddi-tert-butyl dicarbonate (0.504 ml, 2.19 mmol) at room temperature, andstirred for 19 hours. A saturated aqueous sodium hydrogencarbonatesolution and then water were added to the reaction mixture, followed byextraction with chloroform. The organic layer was dried over anhydrousmagnesium sulfate and distilled under reduced pressure to remove thesolvent, and the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate=2/1) to obtain tert-butyl4-hydroxyazepane-1-carboxylate (333 mg, 70%).

¹H-NMR (CDCl₃) δ; 1.50–1.92 (6H, m), 2.39 (1H, s), 3.11–3.42 (4H, m),3.77 (1H, m).

(d) Synthesis of 4-(azepan-4-yloxy)-1H-indazole

4-(Azepan-4-yloxy)-1H-indazol was obtained by carrying out reactionaccording to the method described in Example 320, except for usingtert-butyl 4-hydroxyazepane-1-carboxylate.

Melting point: 187–188° C.

EXAMPLE 323 Synthesis of trans-4-(1H-indazol-4-yloxy)-cyclohexanamine(a) Synthesis oftrans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione

Potassium carbonate (1.64 g, 11.9 mmol) and N-carboethoxyphthalimide(1.59 g, 7.25 mmol) were added to a solution of 4-aminocyclohexanolhydrochloride (1.0 g, 6.59 mmol) in water (15 ml) at room temperatureand stirred for 30 minutes. The reaction solution was filtered and theresulting precipitate was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate=2/1) to obtaintrans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (823 mg, 51%).

¹H-NMR (DMSO-d₆) δ; 1.27 (2H, m), 1.68 (2H, m), 1.88 (2H, m), 2.11 (2H,m), 3.44 (1H, m), 3.94 (1H, m), 4.63 (1H, d, J=4.2 Hz), 7.83 (4H, m).

(b) Synthesis ofcis-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl 4-nitrobenzoate

To a solution oftrans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (359 mg, 1.46mmol) in tetrahydrofuran (15 ml) were added p-nitrobenzoic acid (245 mg,1.46 mmol), triphenylphosphine (422 mg, 1.61 mmol) and a 40%-diethylazodicarboxylate/toluene solution (0.73 ml, 1.61 mmol) at 0° C., andstirred at 0° C. for 30 minutes and then at room temperature for 3hours. The reaction solution was concentrated and the resulting residuewas dissolve in a mixed solution of ethanol (10 ml) and diisopropylether (10 ml) at 60° C. Then, the resulting solution was allowed to cooland the crystals formed were filtered under reduced pressure to obtaincis-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl 4-nitrobenzoate(427 mg, 74%).

¹H-NMR (DMSO-d₆) δ; 1.66 (2H, m), 1.80 (2H, m), 2.05 (2H, m), 2.54 (2H,m), 4.18 (1H, m), 5.23 (1H, m), 7.85 (4H, m), 8.31 (2H, d, J=9.0 Hz),8.40 (2H, d, J=9.0 Hz).

(c) Synthesis of cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione

To a suspension ofcis-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl 4-nitrobenzoate(2.0 g, 5.07 mmol) in a mixture of methanol (40 ml) and tetrahydrofuran(40 ml) was added 28%-sodium methoxide (1.04 ml, 5.07 mmol) at 0° C.,and stirred at 0° C. for 30 minutes and then at room temperature for 3.5hours. The reaction solution was adjusted to pH 4 with a 0.5M-aqueouspotassium hydrogensulfate solution and distilled under reduced pressureto remove the solvent. The residue was added to water and extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent, andthe resulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate=3/1) to obtaincis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (932 mg, 75%).

¹H-NMR (DMSO-d₆) δ; 1.42 (2H, m), 1.48 (2H, m), 1.73 (2H, m), 2.50 (2H,m), 3.85 (1H, m), 3.96 (1H, m), 4.38 (1H, d, J=2.2 Hz), 7.82 (4H, m).

(d) Synthesis of trans-4-(1H-indazol-4-yloxy)-cyclohexanamine

To a solution of the 1H-indazol-4-ol (131 mg, 0.977 mmol) obtained inExample 320, (b) in tetrahydrofuran (10 ml) were added dropwisecis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (215 mg, 0.879mmol), triphenylphosphine (283 mg, 1.07 mmol) and 40%-dibenzylazodicarboxylate-dichloromethane solution (0.672 ml, 1.17 mmol) at 0° C.The resulting mixture was warmed up to room temperature 30 minutes afterthe addition. After stirring overnight, the reaction solution wasconcentrated under reduced pressure and the resulting residue wasdissolved in chloroform (50 ml) and washed with a 1M-aqueous sodiumhydroxide solution (20 ml). Extraction with chloroform (20 ml) wascarried out again, and the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate). To the resultingmixture was added 30%-methylamine/ethanol (2 ml) at room temperature,and the resulting mixture was refluxed for 15 minutes. After 4 hours,the reaction solution was concentrated under reduced pressure at roomtemperature and the resulting residue was purified by a silica gelcolumn chromatography (eluent:chloroform/methanol=10/1→chloroform/methanol/(1%-aqueous ammonia)=10/1)to obtain trans-4-(1H-indazol-4-yloxy)-cyclohexanamine (11 mg, 5.6%).

¹H-NMR (DMSO-d₆) δ; 1.22 (2H, m), 1.48 (2H, m), 1.69 (2H, brs), 1.78(2H, m), 2.07 (2H, m), 2.65 (1H, m), 4.43 (1H, m), 6.56 (1H, d, J=7.5Hz), 7.04 (1H, d, J=7.5 Hz), 7.20 (1H, dd, J=7.5, 7.5 Hz), 7.94 (1H, s),12.97 (1H, s).

The following compounds of Example 324 and Example 325 were synthesizedby carrying out reaction according to the method described in Example323.

EXAMPLE 324 cis-4-(1H-indazol-4-yloxy)-cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 1.44–1.65 (8H, m), 1.94 (2H, m), 2.70 (1H, m), 4.65(1H, m), 6.55 (1H, d, J=7.8 Hz), 7.04 (1H, d, J=7.8 Hz), 7.20 (1H, dd,J=7.8, 7.8 Hz), 8.00 (1H, s), 12.97 (1H, s).

EXAMPLE 325 Synthesis of cis-3-(1H-indazol-4-yloxy)-cyclohexanamine

Melting point: 166–168° C.

EXAMPLE 326 Synthesis of trans-3-(1H-indazol-4-yloxy)-cyclohexanamine(a) Synthesis of 2-(2-cyclohexen-1-yl)-1H-isoindole-1,3 (2H)-dione

Phthalimide (7.08 g, 48.1 mmol), triphenylphosphine (13.2 g, 50.4 mmol)and a 40%-diethyl azodicarboxylate/toluene solution (23.3 ml, 51.4 mmol)were added to a solution of cyclohexenol (4.5 g, 45.9 mmol) intetrahydrofuran (90 ml) at 0° C. and stirred at 0° C. for 30 minutes andthen at room temperature for 2.5 hours. The reaction solution wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate=15/1) to obtain 2-(2-cyclohexen-1-yl)-1H-isoindole-1,3(2H)-dione(3.36 g, 32%).

¹H-NMR (CDCl₃) δ; 1.73 (1H, m), 1.93 (2H, m), 2.16 (3H, m), 4.90 (1H,m), 5.58 (1H, m), 5.94 (1H, m), 7.72 (2H, m), 7.81 (2H, m).

(b) Synthesis of (2S, 6R, 12bS,13S)-13-bromo-12b-propyl-3,4,5,6-tetrahydro-2H-2,6-methano[2,3-a]isoindol-8(12bH)-one

Ethanol (3 ml) and N-bromosuccinimide (2.94 g, 16.5 mmol) were added toa solution of 2-(2-cyclohexen-1-yl)-1H-isoindole-1,3(2H)-dione (3.0 g,13.2 mmol) in chloroform (90 ml) at room temperature and stirred for 14hours. A 1M-aqueous sodium thiosulfate solution was added to thereaction solution, followed by extraction with chloroform. The organiclayer was dried over anhydrous magnesium sulfate and the solvent wasconcentrated under reduced pressure, and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate=10/1) to obtain (2S, 6R, 12bS,13S)-13-bromo-12b-propyl-3,4,5,6-tetrahydro-2H-2,6-methano[2,3-a]isoindol-8(12bH)-one(3.60 g, 77%).

¹H-NMR (CDCl₃) δ; 1.14 (3H, t, J=7.1 Hz), 1.34 (1H, m), 1.68 (2H, m),2.11 (2H, m), 2.54 (1H, m), 3.05 (1H, m), 3.38 (1H, m), 4.37 (1H, m),4.56 (1H, m), 5.57 (1H, m), 7.56 (3H, m), 7.76 (1H, m).

(c) Synthesis of 2-[(1R, 2S,3S)-2-bromo-3-hydroxycyclohexyl]-1H-isoindole-1,3(2H)-dione

A 2N-aqueous hydrochloric acid solution (18 ml) was added to a solutionof (2S, 6R, 12bS,13S)-13-bromo-12b-propyl-3,4,5,6-tetrahydro-2H-2,6-methano[2,3-a]isoindol-8(12bH)-one(3.56 g, 10.1 mmol) in methanol (70 ml) at room temperature and stirredfor 1 hour. The reaction solution was concentrated and the resultingresidue was dissolved in chloroform and washed with water. The organiclayer was dried over anhydrous magnesium sulfate and the solvent wasconcentrated under reduced pressure, and the resulting residue wascrystallized from hexane/ethyl acetate to obtain 2-[(1R, 2S,3S)-2-bromo-3-hydroxycyclohexyl]-1H-isoindole-1,3(2H)-dione (2.19 g,67%).

¹H-NMR (CDCl₃) δ; 1.51 (2H, m), 1.91 (2H, m), 2.20 (2H, m), 2.52 (1H,s), 3.76 (1H, m), 4.38 (1H, m), 4.81 (1H, dd, J=9.5, 11.2 Hz), 7.76 (2H,m), 7.86 (2H, m).

(d) Synthesis of cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione

Tributyltin hydride (1.99 ml, 7.40 mmol) and2,2′-azobis(isobutyronitrile) (8 mg) were added to a solution of 2-[(1R,2S, 3S)-2-bromo-3-hydroxycyclohexyl]-1H-isoindole-1,3(2H)-dione (2.0 g,6.17 mmol) in a mixture of toluene (40 ml) and methanol (4 ml) at roomtemperature, and the resulting mixture was refluxed for 3 hours.Tributyltin hydride (1.99 ml, 7.40 mmol) and2,2′-azobis(isobutyronitrile) (8 mg) were further added thereto, and theresulting mixture was refluxed for 1 hour. The reaction solution wasconcentrated and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate=2/1) to obtaincis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.33 g, 88%).

¹H-NMR (CDCl₃) δ; 1.37 (2H, m), 1.51 (1H, d, J=5.3 Hz), 1.71 (1H, m),1.88 (1H, m), 2.04–2.32 (4H, m), 3.69 (1H, m), 4.17 (1H, m), 7.73 (2H,m), 7.80 (2H, m).

(e) Synthesis of trans-3-(1H-indazol-4-yloxy)-cyclohexanamine

Except for using cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione,trans-3-(1H-indazol-4-yloxy)-cyclohexanamine was synthesized by carryingout reaction according to the method described in Example 323, (d).

¹H-NMR (CDCl₃) δ; 1.14 (1H, m), 1.32–1.58 (3H, m), 1.71 (1H, m), 1.81(1H, m), 1.91 (1H, m), 2.15 (1H, m), 3.19 (1H, m), 4.78 (1H, m), 6.37(1H, d, J=7.7 Hz), 6.95 (1H, d, J=7.7 Hz), 7.12 (1H, dd, J=7.7, 7.7 Hz),8.05 (1H, s).

EXAMPLE 327 Synthesis of trans-3-(1H-indazol-4-yloxy)-cyclohexanaminehydrochloride

To a solution of the trans-3-(1H-indazol-4-yloxy)-cyclohexanamine (163.1mg, 0.705 mmol) obtained in Example 326 in ethanol (3 ml) was added1M-hydrochloric acid/diethyl ether (0.776 ml, 0.776 mmol) at roomtemperature. After 1 hour, the resulting solution was concentrated underreduced pressure, and the resulting oil was crystallized by the additionof acetonitrile, followed by filtration. The precipitate was dried underreduced pressure to obtain trans-3-(1H-indazol-4-yloxy)-cyclohexanaminehydrochloride (166 mg, 88%).

¹H-NMR (DMSO-d₆) δ; 1.39–1.56 (2H, m), 1.71 (3H, m), 1.96 (2H, m), 2.26(1H, m), 3.39 (1H, m), 5.01 (1H, m), 6.59 (1H, d, J=8.2 Hz), 7.08 (1H,d, J=8.2 Hz), 7.23 (1H, dd, J=8.2, 8.2 Hz), 7.92 (3H, brs.), 8.05 (1H,s), 13.03 (1H, s).

EXAMPLE 328 Synthesis of 5-[(4-methylpentyl)oxy]-1H-indazole

To a solution of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained inReference Example 4 in N,N-dimethylformamide (2 ml) were added1-bromo-4-methylpentane (0.109 ml, 0.745 mmol), tetrabutylammoniumiodide (28 mg, 0.1 mmol) and potassium carbonate (103 mg, 0.745 mmol),and the resulting mixture was heated to 60° C. After 9 hours, themixture was poured into water (20 ml) and extracted with ethyl acetate(20 ml×2). The organic layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure, and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain 5-[(4-methylpentyl)oxy]-1H-indazole (60 mg, 37%).

Melting point: 124–126° C.

The following compounds of Example 329 and Example 330 were synthesizedby carrying out reaction according to the method described in Example328.

EXAMPLE 329 5-(Isopentyloxy)-1H-indazole

Melting point: 139–140° C.

EXAMPLE 330 5-Isobutyloxy-1H-indazole

Melting point: 151–153° C.

EXAMPLE 331 Synthesis of 5-(benzyloxy)-1H-indazole

Benzyl bromide (0.089 ml, 0.745 mmol) and potassium carbonate (103 mg,0.745 mmol) were added to a solution of the 1H-indazol-5-ol (100 mg,0.745 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (2ml), and the resulting mixture was heated to 40° C. After 2 hours, themixture was poured into water (20 ml) and extracted with ethyl acetate(20 ml×2). The organic layer was dried over anhydrous magnesium sulfate.The organic layer dried was concentrated under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate) to obtain 5-(benzyloxy)-1H-indazole (63mg, 38%).

Melting point: 179–181° C.

EXAMPLE 332 Synthesis of 5-(piperidin-4-ylmethoxy)-1H-indazoledihydrochloride (a) Synthesis of tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate

A 1M-borane/tetrahydrofuran solution (4.36 ml, 4.36 mmol) was addeddropwise to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylicacid (1.0 g, 4.36 mmol) in tetrahydrofuran (20 ml) at 0° C. After 1hour, the mixture thus obtained was warmed up to room temperature. Afteranother 6 hours, a saturated aqueous sodium hydrogencarbonate solutionwas added to the reaction mixture and the resulting mixture was pouredinto water (100 ml) and extracted with ethyl acetate (50 ml×2). Theorganic layer was dried over anhydrous magnesium sulfate. The organiclayer dried was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate) to obtain tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (715 mg, 76%).

(b) Synthesis of tert-butyl4-[(1H-indazol-5-yloxy)methyl]piperidine-1-carboxylate

Triethylamine (0.155 ml, 1.11 mmol) and methanesulfonyl chloride (0.075ml, 0.975 mmol) were added to a solution of tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (200 mg, 0.929 mmol) indichloromethane (6 ml). After 2 hours, the mixture thus obtained waspoured into water (20 ml), adjusted to pH 4 with a 0.5M-aqueouspotassium hydrogensulfate solution and then extracted with chloroform(20 ml×2). The organic layer was dried over anhydrous magnesium sulfate.The organic layer dried was concentrated under reduced pressure and theresulting residue was dissolved in N,N-dimethylformamide (3 ml). The1H-indazol-5-ol (125 mg, 0.929 mmol) obtained in Reference Example 4,potassium carbonate (128 mg, 0.929 mmol) and tetrabutylammonium bromide(34 mg, 0.0929 mmol) were added thereto, and the resulting mixture washeated to 60° C. After 1 hour, the mixture was heated to 80° C. Afteranother 5 hours, a 1M-aqueous sodium hydroxide solution was addedthereto and the resulting mixture was poured into water (30 ml) andextracted with chloroform (20 ml×2). The organic layer was washed with asaturated aqueous sodium chloride solution and then dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: chloroform/ethyl acetate) to obtaintert-butyl 4-[(1H-indazol-5-yloxy)methyl]piperidine-1-carboxylate (90mg, 29%).

(c) Synthesis of 5-(piperidin-4-ylmethoxy)-1H-indazole dihydrochloride

To tert-butyl 4-[(1H-indazol-5-yloxy)methyl]piperidine-1-carboxylate(81.2 mg, 0.245 mmol) was added 4N-hydrochloric acid-dioxane (1 ml).After 1 hour, the resulting mixture was concentrated under reducedpressure, and the resulting residue was dissolved in methanol (0.5 ml)and crystallized from diethyl ether (10 ml). The crystals were filteredand then dried under reduced pressure to obtain5-(piperidin-4-ylmethoxy)-1H-indazole dihydrochloride (71 mg, 95%).

¹H-NMR (DMSO-d₆) δ; 1.48 (2H, m), 1.90 (2H, m), 2.07 (1H, m), 2.89 (2H,m), 3.27 (2H, m), 3.86 (2H, d, J=6.3 Hz), 7.00 (1H, d, J=9.0 Hz), 7.18(1H, s), 7.42 (1H, d, J=9.0 Hz), 7.92 (1H, s), 8.51 (1H, br), 8.82 (1H,br).

EXAMPLE 333 Synthesis of 5-(2-phenylethoxy)-1H-indazole

Potassium carbonate (68 mg, 0.492 mmol), tetrabutylammonium iodide (17mg, 0.0447 mmol) and phenethyl bromide (0.061 ml, 0.447 mmol) were addedto a solution of the 1H-indazol-5-ol (60 mg, 0.447 mmol) obtained inReference Example 4 in N,N-dimethylformamide (2 ml), and the resultingmixture was heated to 60° C. After 7 hours, chloroform (3 ml) and a1M-aqueous sodium hydroxide solution (4 ml) were added to the reactionmixture and stirred. After removing the aqueous layer, water (3 ml) wasadded to the organic layer and stirred. After removing the aqueouslayer, the organic layer was dried over anhydrous magnesium sulfate. Theorganic layer dried was concentrated and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain 5-(2-phenylethoxy)-1H-indazole (8.4 mg, 8%).

MS: m/z=239 (M+1)

The following compounds of Example 334 to Example 350 were synthesizedby carrying out reaction according to the method described in Example333.

EXAMPLE 334 5-(Cyclopropylmethoxy)-1H-indazole

MS m/z=189 (M+1)

EXAMPLE 335 5-(Cyclobutylmethoxy)-1H-indazole

MS: m/z=203 (M+1)

EXAMPLE 336 5-(Cyclohexylmethoxy)-1H-indazole

MS: m/z=231 (M+1)

EXAMPLE 337 Ethyl(1H-indazol-5-yloxy)acetate

MS: m/z=221 (M+1)

EXAMPLE 338 5-(2-Methoxyethoxy)-1H-indazole

MS m/z=193 (M+1)

EXAMPLE 339 5-(2-Phenoxyethoxy)-1H-indazole

MS: m/z=255 (M+1)

EXAMPLE 340 2-(1H-indazol-5-yloxy)ethanol

MS: m/z=179 (M+1)

EXAMPLE 341 5-(Pyridin-2-ylmethoxy)-1H-indazole

MS: m/z=226 (M+1)

EXAMPLE 342 5-(Pyridin-3-ylmethoxy)-1H-indazole

MS: m/z=226 (M+1)

EXAMPLE 343 5-(Pyridin-4-ylmethoxy)-1H-indazole

MS: m/z=226 (M+1)

EXAMPLE 344 2-[(1H-indazol-5-yloxy)methyl]quinoline

MS: m/z=276 (M+1)

EXAMPLE 345 5-[2-(1H-pyrrol-1-yl)ethoxy]-1H-indazole

MS: m/z=228 (M+1)

EXAMPLE 346 2-[(1H-indazol-5-yloxy)methyl]benzonitrile

MS: m/z=250 (M+1)

EXAMPLE 347 3-[(1H-indazol-5-yloxy)methyl]benzonitrile

Melting point: 158–161° C.

EXAMPLE 348 4-[(1H-indazol-5-yloxy)methyl]benzonitrile

MS: m/z=250 (M+1)

EXAMPLE 349 2-[2-(1H-indazol-5-yloxy)ethyl]-1H-isoindole-1,3(2H)-dione

MS: m/z=308 (M+1)

EXAMPLE 350 2-(Tetrahydro-2H-pyran-2-ylmethoxy)-1H-indazole

MS: m/z=233 (M+1)

EXAMPLE 351 Synthesis of 5-(cyclohexyloxy)-1H-indazole

Cyclohexanol (0.315 ml, 2.98 mmol), triphenylphosphine (442 mg, 1.64mmol) and dibenzyl azodicarboxylate (534 mg, 1.17 mmol) were added at 0°C. to a solution of the 1H-indazol-5-ol (200 mg, 1.49 mmol) obtained inReference Example 4 in tetrahydrofuran (16 ml). After 30 minutes, themixture thus obtained was warmed up to room temperature. After stirringovernight, the reaction solution was concentrated under reduced pressureand a-1M aqueous sodium hydroxide solution (20 ml) was added to theresulting residue, followed by extraction with ethyl acetate (20 ml×2).The organic layer was dried over anhydrous magnesium sulfate. Theorganic layer dried was concentrated under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol, hexane/ethyl acetate) to obtain5-(cyclohexyloxy)-1H-indazole (140 mg, 43%).

Melting point: 144–146° C.

EXAMPLE 352 Synthesis of 5-(2-nitrophenoxy)-1H-indazole

To a solution of the 1H-indazol-5-ol (300 mg, 2.24 mmol) obtained inReference Example 4 in N,N-dimethylformamide (6 ml) were added2-bromonitrobenzene (497 mg, 2.46 mmol) and potassium carbonate (402 mg,2.91 mmol), and the resulting mixture was heated to 120° C. After 6hours, the mixture was poured into water (20 ml) and extracted withethyl acetate (20 ml×2). The organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain5-(2-nitrophenoxy)-1H-indazole (57 mg, 10%).

¹H-NMR (DMSO-d₆) δ; 7.02 (1H, d, J=8.5 Hz), 7.29 (1H, d, J=8.0 Hz), 7.29(1H, dd, J=7.5, 7.5 Hz), 7.46 (1H, s), 7.60 (2H, m), 8.04 (2H, m), 13.18(1H, s)

EXAMPLE 353 Synthesis of 5-(cyclopentyloxy)-1H-indazole

Cyclopentanol (0.068 ml, 0.745 mmol), triphenylphosphine (221 mg, 0.820mmol) and dibenzyl azodicarboxylate (267 mg, 0.895 mmol) were added at0° C. to a solution of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtainedin Reference Example 4 in tetrahydrofuran (6 ml). After 30 minutes, themixture thus obtained was heated to room temperature. After stirringovernight, the reaction solution was concentrated under reduced pressureand a 1M-aqueous sodium hydroxide solution (4 ml) and chloroform (3 ml)were added to the resulting residue. After removing the aqueous layer,water (2 ml) was added to the residue. The aqueous layer was removed andthe organic layer was dried over anhydrous magnesium sulfate. Theorganic layer dried was concentrated and the resulting residue waspurified by a silica gel column chromatography (eluent:chloroform/methanol, hexane/ethyl acetate) to obtain5-(cyclopentyloxy)-1H-indazole (24 mg, 16%).

Melting point: 141–142° C.

The following compounds of Example 354 to Example 360 were synthesizedby carrying out reaction according to the method described in Example353.

EXAMPLE 354 5-(Cycloheptyloxy)-1H-indazole

MS: m/z=231 (M+1)

EXAMPLE 355 5-(1-Methyl-2-phenoxyethoxy)-1H-indazole

MS: m/z=269 (M+1)

EXAMPLE 356 5-(Tetrahydrofuran-3-yloxy)-1H-indazole

MS: m/z=205 (M+1)

EXAMPLE 357 5-(2-Methoxy-1-methylethoxy)-1H-indazole

MS: m/z=207 (M+1)

EXAMPLE 358 5-(Cyclobutyloxy)-1H-indazole

MS: m/z=189 (M+1)

EXAMPLE 359 5-[(2-Methylcyclohexyl)oxy]-1H-indazole

MS: m/z=231 (M+1)

EXAMPLE 360 4-[1-(1H-indazol-5-yloxy)ethyl]benzonitrile

¹H-NMR (CDCl₃) δ; 1.64 (3H, d, J=6.5 Hz), 5.34 (1H, q, J=6.5 Hz), 6.92(1H, d, J=2.2 Hz), 7.10 (1H, dd, J=9.0, 2.2 Hz), 7.36 (1H, d, J=9.0 Hz),7.52 (2H, d, J=8.2 Hz), 7.62 (1H, d, J=8.2 Hz), 7.90 (1H, s), 10.91 (1H,brs.).

EXAMPLE 361 Synthesis of 2-[(1H-indazol-5-yloxy)methyl]benzylamine

Lithium aluminum hydride (44 mg, 1.12 mmol) was added to a solution ofthe 2-[(1H-indazol-5-yloxy)methyl]benzonitrile (70 mg, 0.281 mmol)obtained in Example 346 in tetrahydrofuran (8 ml), and the resultingmixture was refluxed. After 2 hours, water, a 2M-aqueous sodiumhydroxide solution and then water were added to the reaction mixture,and the resulting solution was filtered by the use of Celite. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:chloroform/methanol→chloroform/methanol (1% aqueous ammonia)) to obtain2-[(1H-indazol-5-yloxy)methyl]benzyl-amine (52 mg, 74%).

¹H-NMR (DMSO-d₆) δ; 1.80 (2H, brs.), 3.80 (2H, s), 5.16 (2H, s), 7.08(1H, dd, J=2.2, 8.8 Hz), 7.23 (1H, m), 7.31 (2H, m), 7.45 (3H, m), 7.94(1H, s), 12.90 (1H, brs.).

The following compound of Example 362 was synthesized by carrying outreaction according to the method described in Example 361, except forusing the 4-[(1H-indazol-5-yloxy)methyl]benzonitrile obtained in Example348, as a starting material.

EXAMPLE 362 4-[(1H-indazol-5-yloxy)methyl]benzylamine

Melting point: 197–198° C.

The following compound of Example 363 was synthesized by carrying outreaction according to the method described in Example 361, except forusing the 3-[(1H-indazol-5-yloxy)methyl]benzonitrile obtained in Example347, as a starting material.

EXAMPLE 363 3-[(1H-indazol-5-yloxy)methyl]benzylamine

Melting point: 179–183° C.

The following compound of Example 364 was synthesized by carrying outreaction according to the method described in Example 361, except forusing the 4-[1-(1H-indazol-5-yloxy)ethyl]benzonitrile obtained inExample 360, as a starting material.

EXAMPLE 364 1-{4-[1-(1H-indazol-5-yloxy)ethyl]phenyl}-methanamine

¹H-NMR (CDCl₃) δ; 1.64 (3H, d, J=6.4 Hz), 3.81 (2H, s), 5.29 (1H, q,J=6.4 Hz), 6.97 (1H, d, J=2.2 Hz), 7.06 (1H, dd, J=8.9, 2.2 Hz), 7.26(3H, m), 7.34 (2H, d, J=8.2 Hz), 7.84 (1H, s).

EXAMPLE 365 Synthesis of 5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole

To a solution of the 1H-indazol-5-ol (150 mg, 1.12 mmol) obtained inReference Example 4 in tetrahydrofuran (6 ml) were added4-hydroxytetrahydropyran (0.107 ml, 1.12 mmol), triphenylphosphine (293mg, 1.12 mmol) and a 40%-diethyl azodicarboxylate-toluene solution(0.517 ml, 1.14 mmol) at 0° C. After 30 minutes, the mixture thusobtained was heated to room temperature. After stirring overnight, thereaction solution was concentrated under reduced pressure, and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol) to obtain5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole (11.4 mg, 47%).

Melting point: 151–153° C.

EXAMPLE 366 Synthesis of 5-[(1-isopropylpiperidin-4-yl)oxy]-1H-indazole

The 5-(piperidin-4-yloxy)-1H-indazole (80 mg, 0.368 mmol) obtained inExample 42 was suspended in methanol (2 ml), and acetone (0.031 ml, 1.10mmol) and acetic acid (0.105 ml, 1.84 mmol) were added dropwise thereto.Then, sodium cyanoborohydride (116 mg, 1.84 mmol) was added thereto.After 18 hours, acetone, acetic acid and sodium cyanoborohydride werefurther added in the same amounts, respectively, as above. After 3 days,a saturated aqueous sodium hydrogencarbonate solution was added to thereaction solution, and the resulting mixture was poured into water (20ml) and extracted with chloroform (20 ml×3). The organic layer was driedover anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent:chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain5-[(1-isopropylpiperidin-4-yl)oxy]-1H-indazole (30 mg, 31%).

Melting point: 125–126° C.

EXAMPLE 367 Synthesis of Ethyl4-(1H-indazol-5-yloxy)cyclohexanecarboxylate

Ethyl 4-hydroxycyclohexylcarboxylate (1.44 ml, 8.95 mmol),triphenylphosphine (2.15 g, 8.20 mmol) and dibenzyl azodicarboxylate(3.34 g, 11.18 mmol) were added at 0° C. to a solution of the1H-indazol-5-ol (1.0 g, 7.45 mmol) obtained in Reference Example 4 intetrahydrofuran (40 ml). After 1 hour, the mixture thus obtained waswarmed up to room temperature. After stirring overnight, the reactionsolution was concentrated under reduced pressure, and the resultingresidue was purified by a silica gel column chromatography (eluent:chloroform/ethyl acetate, hexane/ethyl acetate) to obtain ethyl4-(1H-indazol-5-yloxy)cyclohexanecarboxylate (928 mg, 43%).

MS: m/z=289 (M+1)

EXAMPLE 368 Synthesis of 4-(1H-indazol-5-yloxy)cyclohexanecarboxylicacid

The ethyl 4-(1H-indazol-5-yloxy)cyclo-hexanecarboxylate (728.4 mg, 2.53mmol) obtained in Example 367 was dissolved in a mixture of methanol(2.5 ml) and tetrahydrofuran (2.5 ml), and a 2M-aqueous lithiumhydroxide solution (2.53 ml, 5.05 mmol) was added dropwise thereto.After 2 hours, the reaction mixture was concentrated under reducedpressure and the resulting residue was dissolved in water (5 ml). Theresulting aqueous solution was adjusted to pH 4 with a 0.5M-aqueouspotassium hydrogensulfate solution. The crystals formed were filteredunder reduced pressure and then dried to obtain4-(1H-indazol-5-yloxy)cyclohexanecarboxylic acid (381 mg, 58%).

¹H-NMR (DMSO-d₆) δ; 1.47 (2H, m), 1.65 (2H, m), 1.78 (4H, m), 1.91 (1H,m), 2.10 (1H, m), 2.24 (0.5H, m), 2.36 (0.5H, m), 4.24 (0.5H, m), 4.47(0.5H, m), 6.98 (1H, m), 7.21 (1H, m), 7.40 (1H, m), 7.90 (1H, s), 12.84(1H, br).

EXAMPLE 369 Synthesis of 4-(1H-indazol-5-yloxy)cyclohexanecarboxamide

Ammonium chloride (173 ml, 3.23 mmol) and diisopropylethylamine (0.75ml, 4.30 mmol) were added to a solution of the4-(1H-indazol-5-yloxy)cyclohexanecarboxylic acid (280 mg, 1.08 mmol)obtained in Example 368 in N,N-dimethylformamide (10 ml). After aqueousammonia (1 ml) was added thereto to effect dissolution,1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (309mg, 1.61 mmol) and hydroxybenzotriazole (160 mg, 1.18 mmol) were addedthereto. After 16 hours, it was confirmed that the starting materialremained. Therefore, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidemonohydrochloride (309 mg, 1.61 mmol) and hydroxybenzotriazole (160 mg,1.18 mmol) were further added thereto. After 7 hours, a saturatedaqueous sodium hydrogencarbonate solution was added to the reactionsolution, and the resulting mixture was poured into water (100 ml) andextracted with ethyl acetate (50 ml×3) and chloroform (20 ml×2). Theorganic layer was washed with a saturated aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The organiclayer dried was concentrated under reduced pressure and the resultingresidue was washed with diethyl ether by repulping to obtain4-(1H-indazol-5-yloxy)cyclohexanecarboxamide (265 mg, 95%).

¹H-NMR (DMSO-d₆) δ; 1.45 (1H, m), 1.66 (3H, m), 1.94 (2H, m), 2.11 (1H,m), 2.26 (2H, m), 4.35 (0.5H, m), 4.65 (0.5H, m), 6.85 (1H, s), 7.15(1H, m), 7.37 (2H, m), 7.56 (1H, m), 8.05 (1H, s), 13.01 (1H, s).

EXAMPLE 370 Synthesis of [4-(1H-indazol-5-yloxy)cyclohexyl]methanol

Lithium aluminum hydride (52 mg, 1.39 mmol) was added to a solution ofthe ethyl 4-(1H-indazol-5-yloxy)cyclohexanecarboxylate (100 mg, 0.347mmol) obtained in Example 367 in tetrahydrofuran (2 ml), and theresulting mixture was refluxed. After 2 hours, water (52 μl), a2M-aqueous sodium hydroxide solution (0.104 ml) and then water (0.156ml) were added to the reaction mixture, and the resulting solution wasfiltered by the use of Celite. The filtrate was concentrated underreduced pressure, and the resulting oil was crystallized by the additionof diisopropyl ether. The crystals were filtered under reduced pressureand then dried to obtain [4-(1H-indazol-5-yloxy)cyclohexyl]methanol (72mg, 84%, trans/cis=4/1).

¹H-NMR (DMSO-d₆): 1.04 (1.6H, m), 1.33 (3.8H, m), 1.79 (1.6H, m), 1.95(0.4H, m), 2.11 (1.6H, m), 3.24 (2H, m), 4.18 (0.8H, m), 4.42 (1H, m),4.55 (0.2H, m), 7.01 (1H, m), 7.19 (1H, s), 7.39 (1H, m), 7.90 (1H, s),12.85 (1H, s).

EXAMPLE 371 Synthesis of 1-[4-(1H-indazol-5-yloxy)cyclohexyl]methanamine

Lithium aluminum hydride (58 mg, 1.54 mmol) was added to a solution ofthe 4-(1H-indazol-5-yloxy)cyclohexanecarboxamide (100 mg, 0.386 mmol)obtained in Example 369 in tetrahydrofuran (3 ml), and the resultingmixture was refluxed. After 6 hours, water (0.087 ml), a 2M-aqueoussodium hydroxide solution (0.176 ml) and then water (0.261 ml) wereadded to the reaction mixture, and the resulting solution was filteredby the use of Celite. The filtrate was concentrated under reducedpressure, and the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol→chloroform/methanol(1%-aqueous ammonia)) to obtain1-[4-(1H-indazol-5-yloxy)cyclohexyl]methanamine (49 mg, 52%).

¹H-NMR (DMSO-d₆) δ; 1.02 (2H, m), 1.28 (3H, m), 1.52 (2H, m), 1.79 (2H,m), 2.08 (2H, m), 2.39 (2H, m), 4.18 (1H, m), 6.98 (1H, dd, J=9.0, 2.0Hz), 7.19 (1H, d, J=2.0 Hz), 7.38 (1H, d, J=9.0 Hz), 7.90 (1H, s), 12.87(1H, s)

EXAMPLE 372 Synthesis of 4-(1H-indazol-5-yloxy)cyclo-hexanol (a)Synthesis of 4-(tetrahydro-2H-pyran-2-yloxy)cyclo-hexanol

An acidic resin (Dowex 50W×8, trade name, Dow Chemical Company, 800 mg)and dihydropyran (1.89 ml, 20.7 mol) were added dropwise to a solutionof 1,4-cyclohexanediol (4.0 g, 34.4 mol) in toluene (80 ml) at roomtemperature and vigorously stirred. After 17 hours, the reaction mixturewas filtered by the use of Celite and the filtrate was concentratedunder reduced pressure. The resulting residue was purified by a silicagel column chromatography (eluent: hexane/ethyl acetate) to obtain4-(tetrahydro-2H-pyran-2-yloxy)cyclo-hexanol (2.69 g, 65%).

(b) Synthesis of5-{[4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]oxy}-1H-indazole

To a solution of the 1H-indazol-5-ol (250 mg) obtained in ReferenceExample 4 in tetrahydrofuran (15 ml) were added4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanol (373 mg, 1.86 mmol),triphenylphosphine (538 mg, 2.05 mmol) and dibenzyl azodicarboxylate(667 mg, 2.24 mmol) at 0° C. After 1 hour, the mixture thus obtained washeated to room temperature. After stirring overnight, the reactionsolution was concentrated under reduced pressure, and a 1M-aqueoussodium hydroxide solution (50 ml) was added to the resulting residue,followed by extraction with chloroform (50 ml×2). The organic layer waswashed with a saturated aqueous sodium chloride solution and then driedover anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure, and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain5-{[4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]oxy}-1H-indazole (244 mg,41%).

(c) Synthesis of 4-(1H-indazol-5-yloxy)cyclohexanol

An acidic resin (Dowex 50W×8, trade name, Dow Chemical Company, 46 mg)was added to a solution of5-{[4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]oxy}-1H-indazole (232 mg,0.733 mmol) in methanol (10 ml), and the resulting mixture was heated to50° C. After 5 hours, the reaction solution was filtered by the use ofCelite and the filtrate was concentrated under reduced pressure. Theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol) to obtain4-(1H-indazol-5-yloxy)cyclohexanol (132 g, 78%).

Melting point: 112–118° C.

The following compound of Example 373 was synthesized by carrying outreaction according to the method described in Example 372, except forusing 1,3-cyclohexanediol as a starting material.

EXAMPLE 373 3-(1H-indazol-5-yloxy)cyclohexanol

¹H-NMR (DMSO-d₆) δ; 1.04–1.37 (2.5H, m), 1.60–1.78 (5H, m), 1.99 (0.5H,m), 3.51 (0.5H, m), 3.89 (0.5H, m), 4.20 (0.5H, m), 4.51 (0.5H, d, J=4.0Hz), 4.61 (0.5H, m), 4.64 (0.5H, d, J=4.6 Hz), 6.98 (1H, dd, J=2.4, 9.0Hz), 7.18 (1H, m), 7.39 (1H, d, J=9.0 Hz), 7.91 (1H, s), 12.86 (1H, s)

The following compound of Example 374 was synthesized by carrying outreaction according to the method described in Example 372, except forusing 1,3-cyclopentanediol as a starting material.

EXAMPLE 374 3-(1H-indazol-5-yloxy)cyclopentanol

Melting point: 147–148° C.

EXAMPLE 375 Synthesis of 2-[4-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol

To a solution of the 5-(piperidin-4-yloxy)-1H-indazole (31 mg, 0.143mmol) obtained in Example 42 in N,N-dimethylformamide (1 ml) were added2-bromoethanol (0.0121 ml, 0.171 mmol) and potassium carbonate (49 mg,0.357 mmol). After 17 hours, 2-bromoethanol (0.0121 ml, 0.171 mmol) wasfurther added thereto. After another 24 hours, the reaction mixture wasfiltered by the use of Celite and the filtrate was concentrated underreduced pressure. The resulting residue was purified by a silica gelcolumn chromatography (eluent:chloroform/methanol→chloroform/methanol/(1%-aqueous ammonia)) to obtain2-[4-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol (14 mg, 38%).

¹H-NMR (DMSO-d₆) δ; 1.62 (2H, m), 1.9 (2H, m), 2.25 (2H, m), 2.39 (2H,t), 2.73 (2H, m), 3.47 (2H, dt), 4.30 (1H, m), 4.36 (1H, t), 7.00 (1H,d), 7.21 (1H, s), 7.49 (1H, d), 7.90 (1H, s), 12.87 (1H, s).

The following compound of Example 376 was synthesized by carrying outreaction according to the method described in Example 372, (b).

EXAMPLE 376 tert-Butyl 3-(1H-indazol-5-yloxy)piperidine-1-carboxylate

¹H-NMR (DMSO-d₆) δ; 1.22–1.37 (10H, m), 1.72 (2H, m), 1.92 (1H, m), 3.32(2H, m), 3.55 (2H, m), 5.32 (1H, m), 7.00 (1H, dd, J=2.3, 9.0 Hz), 7.22(1H, d, J=2.3 Hz), 7.42 (1H, d, J=9.0 Hz), 7.91 (1H, s), 12.89 (1H,brs).

EXAMPLE 377 Synthesis of 5-(piperidin-3-yloxy)-1H-indazole

To a solution of the tert-butyl3-(1H-indazol-5-yloxy)piperidine-1-carboxylate (150 mg, 0.473 mmol)obtained in Example 376 in methanol (2 ml) was added a 4N-hydrochloricacid-dioxane solution (1 ml) at room temperature. After 3 hours, themixture thus obtained was concentrated under reduced pressure, and theresulting residue was dissolved in methanol. The resulting solution wasadjusted to pH 8 to 9 with a 2M-aqueous sodium hydroxide solution andconcentrated under reduced pressure. The residue was purified by asilica gel column chromatography (eluent:chloroform/methanol/chloroform/methanol/(1%-aqueous ammonia)) to obtain5-(piperidin-3-yloxy)-1H-indazole (104 mg, 65%).

¹H-NMR (DMSO-d₆) δ; 1.55 (2H, m), 1.74 (1H, m), 1.98 (1H, m), 2.70 (2H,m), 2.85 (1H, m), 3.16 (1H, m), 4.34 (1H, m), 7.04 (1H, dd, J=2.2, 9.0Hz), 7.25 (1H, d, J=2.2 Hz), 7.42 (1H, d, J=9.0 Hz), 7.92 (1H, s), 12.92(1H, s).

The following compound of Example 378 was synthesized by carrying outreactions according to the methods described in Example 372, (b) andExample 377, except for using tert-butyl3-hydroxypyrrolidine-1-carboxylate as a reagent.

EXAMPLE 378 5-(Pyrrolidin-3-yloxy)-1H-indazole

¹H-NMR (DMSO-d₆) δ; 2.08 (2H, m), 3.17–3.38 (5H, m), 5.04 (1H, m), 7.02(1H, dd, J=2.2, 9.0 Hz), 7.23 (1H, d, J=2.2 Hz), 7.45 (1H, d, J=9.0 Hz),7.95 (1H, s), 12.97 (1H, s).

The following compound of Example 379 was synthesized by carrying outreactions according to the methods described in Example 372, (b) andExample 377 except for using the tert-butyl4-hydroxyazepane-1-carboxylate obtained in Example 322, (c), as areagent.

EXAMPLE 379 5-(Azepan-4-yloxy)-1H-indazole

Melting point: 159–160° C.

The following compound of Example 380 was synthesized by carrying outreaction according to the method described in Example 372, (b), exceptfor using the trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 323, (a), as a starting material.

EXAMPLE 380cis-2-[4-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione

Melting point: 194–196° C.

EXAMPLE 381 Synthesis of cis-4-(1H-indazol-5-yloxy)cyclo-hexanamine

A 30%-methylamine-ethanolamine solution (1.0 ml) was added to thecis-2-[4-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione (100mg, 0.277 mmol) obtained in Example 380. After 22 hours, the mixturethus obtained was poured into water (20 ml) and extracted with ethylacetate (20 ml×2), and the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure, and the resulting residue was purified by a silica gelcolumn chromatography (eluent:chloroform/methanol→chloroform/methanol/(1%-aqueous ammonia)) to obtaincis-4-(1H-indazol-5-yloxy)cyclo-hexanamine (36 mg, 57%).

Melting point: 144–146° C.

The following compound of Example 382 was synthesized by carrying outreaction according to the method described in Example 372, (b), exceptfor using the cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 326, (d), as a reagent.

EXAMPLE 382trans-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione

Melting point: 197–198° C.

The following compound of Example 383 was synthesized by carrying outreaction according to the method described in Example 381, except forusing thecis-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dionesynthesized in Example 382, as a starting material.

EXAMPLE 383 trans-3-(1H-indazol-5-yloxy)cyclohexanamine

Melting point: 179–180° C.

The following compound of Example 384 was synthesized by carrying outreactions according to the methods described in Example 372, (b) andExample 381, except for using thecis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 323, (c), as a starting material.

EXAMPLE 384 trans-4-(1H-indazol-5-yloxy)cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 1.16 (2H, m), 1.34 (2H, m), 1.69 (2H, brs), 1.76(2H, m), 2.01 (2H, m), 2.64 (1H, m), 4.19 (1H, m), 6.97 (1H, dd, J=2.4,9.0 Hz), 7.19 (1H, d, J=2.4 Hz), 7.38 (1H, d, J=9.0 Hz), 7.90 (1H, s),12.87 (1H, s).

EXAMPLE 385 Synthesis of cis-3-(1H-indazol-5-yloxy)cyclo-hexanamine (a)Synthesis of trans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl4-nitrobenzoate

Except for using thecis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 326, (d),trans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl4-nitrobenzoate was obtained by carrying out reaction according to themethod described in Example 323, (b).

(b) Synthesis oftrans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione

Except for usingtrans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl4-nitrobenzoate,trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione was obtained bycarrying out reaction according to the method described in Example 323,(c).

(c) Synthesis of cis-3-(1H-indazol-5-yloxy)cyclohexanamine

To a solution of the 1H-indazol-5-ol (200 mg, 1.49 mmol) obtained inReference Example 4 in tetrahydrofuran (15 ml) were added dropwisetrans-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione(366 mg, 1.49 mmol), triphenylphosphine (430 mg, 1.64 mmol) and a40%-dibenzyl azodicarboxylate-dichloromethane solution (1.03 ml, 1.79mmol) at 0° C. After 1 hour, the mixture thus obtained was warmed up toroom temperature. After stirring overnight, the reaction solution wasconcentrated under reduced pressure, and the resulting residue wasdissolved in chloroform (50 ml) and washed with a 1M-aqueous sodiumhydroxide solution (20 ml). Extraction with chloroform (20 ml) wascarried out again and the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain amixture. To this mixture was added 30%-methylamine/ethanol (6 ml) undera nitrogen atmosphere at room temperature, after 15 minutes, then theresulting mixture was refluxed. After 3 hours, the reaction mixture wasconcentrated under reduced pressure at room temperature and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol→chloroform/methanol/(1% aqueous ammonia))to obtain cis-3-(1H-indazol-5-yloxy)cyclohexanamine (98 mg, 29%).

¹H-NMR (DMSO-d₆) δ; 0.92–1.32 (4H, m), 1.45 (2H, s), 1.68 (2H, m), 2.04(1H, m), 2.17 (1H, m), 2.63 (1H, m), 4.20 (1H, m), 6.98 (1H, dd, J=2.4,9.0 Hz), 7.19 (1H, d, J=2.4 Hz), 7.39 (1H, d, J=9.0 Hz), 7.90 (1H, s),12.87 (1H, s).

The following compounds of Example 386 and Example 387 were synthesizedby carrying out reaction according to the method described in Example140, except for using the trans-4-(1H-indazol-5-yloxy)cyclohexanamineobtained in Example 384, as a starting material.

EXAMPLE 386 trans-N-butyl-4-(1H-indazol-5-yloxy)cyclohexanamine

MS: m/z=288 (M+1)

EXAMPLE 387 trans-4-(1H-indazol-5-yloxy)-N-isopropylcyclohexanamine

MS: m/z=274 (M+1)

EXAMPLE 388 trans-N-cyclopentyl-4-(1H-indazol-5-yloxy)cyclohexanamine

MS: m/z=300 (M+1)

EXAMPLE 389 Synthesis oftrans-4-(1H-indazol-5-yloxy)-N,N-dimethylcyclohexanaminemonohydrochloride

Acetic acid (0.05 ml, 0.87 mmol) was added to a solution of thetrans-4-(1H-indazol-5-yloxy)cyclohexanamine (0.044 g, 0.19 mmol)obtained in Example 384 and paraformaldehyde (0.040 g, 1.33 mmol) inmethanol (4 ml), and the resulting mixture was stirred for 15 minutesand then ice-cooled. Sodium cyanoborohydride (0.055 g, 0.87 mmol) wasadded thereto and the resulting mixture was slowly warmed up to roomtemperature and stirred overnight. After a 1N-aqueous sodium hydroxidesolution was added thereto, the solvent was distilled off under reducedpressure and the residue was dried up and then purified by a silica gelchromatography (eluent: chloroform/methanol/30%-aqueousammonia=300/10/3). A solution of the purified residue in ethyl acetatewas prepared, followed by adding thereto a 1N-hydrochloric acid-diethylether solution (0.5 ml). The solid precipitated was subjected todecantation with ethyl acetate (three times) and then dried up to obtaintrans-4-(1H-indazol-5-yloxy)-N,N-dimethylcyclohexanaminemonohydrochloride (0.0400 g, 86%).

MS: m/z=260 (M+1)

The following compound of Example 390 was synthesized by carrying outreaction according to the method described in Example 389.

EXAMPLE 390

trans-4-(1H-indazol-5-yloxy)-N-propylcyclohexanamine monohydrochloride

MS: m/z=274 (M+1)

EXAMPLE 391 Synthesis oftrans-N-[4-(1H-indazol-5-yloxy)cyclohexyl]acetamide

Acetic acid (0.033 g, 0.58 mmol), triethylamine (0.12 ml, 0.86 mmol),1-hydroxybenztriazole (0.088 g, 0.65 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.124g, 0.65 mmol) were added to a solution of thetrans-4-(1H-indazol-5-yloxy)cyclohexanamine (0.100 g, 0.44 mmol)obtained in Example 384 in N,N-dimethylformamide (5 ml) and stirredovernight. A 2N-aqueous lithium hydroxide solution (2 ml) was addedthereto and stirred for some time, and the resulting mixture was addedto water and extracted three times with toluene/ethyl acetate=1/1. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure and the solid precipitated wassuspended in a hexane/ethyl acetate mixed solvent and stirred to bewashed. The solid was collected by filtration and dried under reducedpressure to obtain trans-N-[4-(1H-indazol-5-yloxy)cyclohexyl]acetamide(0.097 g, 82%).

MS: m/z=274 (M+1)

EXAMPLE 392 Synthesis oftrans-N-ethyl-4-(1H-indazol-5-yloxy)cyclohexanamine monohydrochloride

The trans-N-[4-(1H-indazol-5-yloxy)cyclohexyl]acetamide (0.066 g, 0.24mmol) obtained in Example 391 was added to a suspension of lithiumaluminum hydride (0.040 g, 1.05 mmol) in tetrahydrofuran (5 ml) andstirred for 12 hours with heating under reflux. The resulting solutionwas cooled on an ice bath, followed by adding dropwise thereto water(0.05 ml), a 2N-aqueous sodium hydroxide solution (0.10 ml) and water(0.15 ml) in that order. Thereafter, the insoluble material was removedby filtration using Celite. The filtrate was purified by a silica gelchromatography (eluent: chloroform/methanol/30%-aqueous ammonia=10/1/0to 100/10/1). A solution of the purified material in ethyl acetate wasprepared and a 1N-hydrochloric acid/diethyl ether solution (0.5 ml) wasadded thereto. The solid precipitated was subjected to decantation withethyl acetate and dried up to obtaintrans-N-ethyl-4-(1H-indazol-5-yloxy)cyclohexanamine monohydrochloride(0.057 g, 80%).

MS: m/z=260 (M+1)

The following compounds of Example 393 to Example 397 were synthesizedby carrying out reaction according to the method described in Example140, except for using the trans-3-(1H-indazol-5-yloxy)cyclohexanamineobtained in Example 383, as a starting material.

EXAMPLE 393 trans-3-(1H-indazol-5-yloxy)-N,N-dimethylcyclohexanamine

Melting point: 134–135° C.

EXAMPLE 394 trans-3-(1H-indazol-5-yloxy)-N-propylcyclohexanamine

MS: m/z=274 (M+1)

EXAMPLE 395 trans-N-butyl-3-(1H-indazol-5-yloxy)cyclohexanamine

MS: m/z=288 (M+1)

EXAMPLE 396 trans-3-(1H-indazol-5-yloxy)-N-isopropylcyclohexanamine

MS: m/z=274 (M+1)

EXAMPLE 397 trans-N-cyclopentyl-3-(1H-indazol-5-yloxy)cyclohexanamine

MS: m/z=300 (M+1)

The following compound of Example 398 was synthesized by carrying outreaction according to the method described in Example 391, except forusing the trans-3-(1H-indazol-5-yloxy)cyclohexanamine obtained inExample 383, as a starting material.

EXAMPLE 398 trans-N-[3-(1H-indazol-5-yloxy)cyclohexyl]-acetamide

MS: m/z=274 (M+1)

EXAMPLE 399 Synthesis oftrans-N-ethyl-3-(1H-indazol-5-yloxy)cyclohexanamine

The trans-N-[3-(1H-indazol-5-yloxy)cyclohexyl]-acetamide (0.077 g, 0.28mmol) obtained in Example 398 was added to a suspension of lithiumaluminum hydride (0.040 g, 1.05 mmol) in tetrahydrofuran (5 ml) andstirred for 12 hours with heating under reflux. The resulting solutionwas cooled on an ice bath, followed by adding dropwise thereto water(0.05 ml), a 2N-aqueous sodium hydroxide solution (0.10 ml) and water(0.15 ml) in that order. Thereafter, the insoluble material was removedby filtration using Celite. The filtrate was purified by a silica gelchromatography (eluent: chloroform/methanol/30%-aqueous ammonia=10/1/0to 100/10/1) to obtaintrans-N-ethyl-3-(1H-indazol-5-yloxy)cyclohexanamine (0.060 g, 83%).

Melting point: 116–118° C.

EXAMPLE 400 Synthesis oftrans-N,N-diethyl-3-(1H-indazol-5-yloxy)cyclohexanaminemonohydrochloride (a) Synthesis oftrans-N-ethyl-N-[3-(1H-indazol-5-yloxy)cyclohexyl]acetamide

The title compound was synthesized by carrying out reaction according tothe method described in Example 391, except for using thetrans-N-ethyl-3-(1H-indazol-5-yloxy)cyclohexanamine obtained in Example399, as a starting material.

(b) Synthesis of trans-N,N-diethyl-3-(1H-indazol-5-yloxy)cyclohexanaminemonohydrochloride

Except for usingtrans-N-ethyl-N-[3-(1H-indazol-5-yloxy)cyclohexyl]acetamide,trans-N,N-diethyl-3-(1H-indazol-5-yloxy)cyclohexanaminemonohydrochloride was obtained by carrying out reaction according to themethod described in Example 392.

MS: m/z=288 (M+1)

EXAMPLE 401 Synthesis of 5-methoxy-4-methyl-1H-indazole (a) Synthesis ofN-(4-methoxy-2,3-dimethylphenyl)acetamide

To a solution of 2,3-dimethyl-4-nitroanisole (1.04 g, 5.74 mmol) inmethanol (20 ml) was added 10%-Pd/C (100 mg) at room temperature, andthe resulting solution was stirred under a hydrogen atmosphere. After 1hour, the reaction solution was filtered by the use of Celite and thefiltrate was concentrated under reduced pressure and then dried. Theresidue was dissolved in ethyl acetate (10 ml), followed by addingthereto acetic anhydride (0.867 ml, 9.18 mmol), and the resultingmixture was refluxed. After 2 hours, hexane (70 ml) was poured into thereaction solution and the crystals formed were filtered under reducedpressure and then dried to obtainN-(4-methoxy-2,3-dimethylphenyl)acetamide (1.02 g, 92%).

(b) Synthesis of 5-methoxy-4-methyl-1H-indazole

Acetic anhydride (1.46 ml, 15.52 mmol), tetrabutylammonium bromide (83mg, 0.259 mmol), potassium acetate (1.02 g, 10.35 mmol) and isoamylnitrite (0.904 ml, 6.73 mmol) were added to a solution ofN-(4-methoxy-2,3-dimethylphenyl)acetamide (1.0 g, 5.175 mmol) in ethylacetate (10 ml) at room temperature, and the resulting mixture wasrefluxed. After 6 hours, the ethyl acetate was distilled off withheating, and a 6M-aqueous sodium hydroxide solution (10.35 ml, 62.1mmol) was added dropwise to the residue at 60° C. After 1 hour, thereaction solution was adjusted to pH 8 to 9 with a 3M-aqueoushydrochloric acid solution and extracted with chloroform (50 ml×2), andthe organic layer was dried over anhydrous magnesium sulfate. Theorganic layer dried was concentrated under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate) to obtain 5-methoxy-4-methyl-1H-indazole(456 mg, 54%).

Melting point: 148–149° C.

EXAMPLE 402 Synthesis of 4-methyl-1H-indazol-5-ol

A solution of boron tribromide (0.513 ml, 5.43 mmol) in dichloromethane(5 ml) was added dropwise to a solution of the5-methoxy-4-methyl-1H-indazole (400 mg, 2.47 mmol) obtained in Example401 in dichloromethane (5 ml) at 0° C. After 1 hour, the reactionsolution was poured onto ice (50 ml), adjusted to pH 4 to 5 with asaturated aqueous sodium hydrogencarbonate solution, and then extractedwith chloroform (20 ml×2) and ethyl acetate (20 ml×2), and the organiclayer was dried over anhydrous magnesium sulfate. The organic layerdried was concentrated under reduced pressure and the resulting residuewas purified by a silica gel column chromatography (eluent:chloroform/ethyl acetate) to obtain 4-methyl-1H-indazol-5-ol (149 mg,41%).

¹H-NMR (DMSO-d₆) δ; 2.31 (3H, s), 6.93 (1H, d, J=8.8 Hz), 7.13 (1H, d,J=8.8 Hz), 7.90 (1H, s), 8.72 (1H, s), 12.68 (1H, s).

EXAMPLE 403 Synthesis of 6-methyl-1H-indazol-5-ol (a) Synthesis of4-(acetylamino)-2,5-dimethylphenyl acetate

Acetic anhydride (0.894 ml, 9.48 mmol) and pyridine (1 ml) were added toa solution of 2,5-dimethy-4-aminophenol (500 mg, 3.64 mmol) in ethylacetate (5 ml), and the resulting mixture was refluxed. After 1 hour,hexane (50 ml) was poured into the reaction solution and the crystalsformed were filtered under reduced pressure and then dried to obtain4-(acetylamino)-2,5-dimethylphenyl acetate (763 mg, 95%).

(b) Synthesis of 1-acetyl-6-methyl-1H-indazol-5-yl acetate

Acetic anhydride (0.96 ml, 10.2 mmol), tetrabutylammonium bromide (55mg, 0.169 mmol), potassium acetate (665 mg, 6.78 mmol) and isoamylnitrite (0.592 ml, 4.41 mmol) were added to a solution of4-(acetylamino)-2,5-dimethylphenyl acetate (750 mg, 3.39 mmol) in ethylacetate (7.5 ml) at room temperature, and the resulting mixture wasrefluxed. After 9 hours, the reaction solution was poured into water (50ml) and extracted with ethyl acetate (50 ml×2), and the organic layerwas dried over anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain 1-acetyl-6-methyl-1H-indazol-5-yl acetate (359 mg,46%).

(c) Synthesis of 6-methyl-1H-indazol-5-ol

A 2M-aqueous lithium hydroxide solution (1.46 ml, 2.93 mmol) was addeddropwise to a solution of 1-acetyl-6-methyl-1H-indazol-5-yl acetate (340mg, 1.46 mmol) in a mixture of methanol (2.0 ml) and tetrahydrofuran(1.0 ml) at room temperature. After 1 hour, the reaction mixture wasadjusted to pH 4 with a 0.5M-aqueous potassium hydrogensulfate solution.The resulting solution was poured into water (50 ml) and extracted withethyl acetate (30 ml×3), and the extract solution was dried overanhydrous magnesium sulfate. The extract solution dried was concentratedunder reduced pressure and the resulting residue was purified by asilica gel column chromatography (eluent: hexane/ethyl acetate) toobtain 6-methyl-1H-indazol-5-ol (199 mg, 92%).

¹H-NMR (DMSO-d₆) δ; 2.22 (3H, s), 6.95 (1H, s), 7.20 (1H, s), 7.76 (1H,s), 9.05 (1H, s), 12.57 (1H, brs).

The following compound of Example 404 was synthesized by carrying outreactions according to the methods described in Example 372, (b) andExample 377, except for using the 4-methyl-1H-indazol-5-ol synthesizedin Example 402, as a starting material.

EXAMPLE 404 Synthesis of 4-methyl-5-(piperidin-4-yloxy)-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.78 (2H, m), 2.00 (2H, m), 2.40 (3H, s), 2.89 (2H,m), 3.14 (2H, m), 4.35 (1H, m), 7.15 (1H, d, J=9.0 Hz), 7.28 (1H, d,J=9.0 Hz), 8.03 (1H, s), 12.92 (1H, brs).

The following compound of Example 405 was synthesized by carrying outreactions according to the methods described in Example 372, (b) andExample 377, except for using the 6-methyl-1H-indazol-5-ol synthesizedin Example 403, as a starting material.

EXAMPLE 405 Synthesis of 6-methyl-5-(piperidin-4-yloxy)-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.51 (2H, m), 1.92 (2H, m), 2.26 (3H, s), 2.57 (2H,m), 2.93 (2H, m), 4.38 (1H, m), 7.16 (1H, s), 7.28 (1H, s), 7.84 (1H,s), 12.70 (1H, brs)

The following compound of Example 406 was synthesized by carrying outreactions according to the methods described in Example 372, (b) andExample 377, except for using the 6-methyl-1H-indazol-5-ol synthesizedin Example 403, as a starting material.

EXAMPLE 406 Synthesis of 6-methyl-5-(piperidin-3-yloxy)-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.45 (2H, m), 1.68 (1H, m), 2.04 (1H, m), 2.25 (3H,s), 2.59 (2H, m), 3.10 (1H, m), 4.20 (1H, m), 7.17 (1H, s), 7.28 (1H,s), 7.85 (1H, s), 12.71 (1H, s).

The following compound of Example 407 was synthesized by carrying outreactions according to the methods described in Example 372, (b) andExample 377, except for using the 4-methyl-1H-indazol-5-ol synthesizedin Example 402, as a starting material.

EXAMPLE 407 Synthesis of 5-(azepin-4-yloxy)-4-methyl-1H-indazole

Melting point: 157–159° C.

The following compound of Example 408 was synthesized by carrying outreaction according to the method described in Example 385, except forusing the cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 323, (c) and the 4-methyl-1H-indazol-5-ol obtainedin Example 402, as starting materials.

EXAMPLE 408 trans-4-[(4-Methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 150–152° C.

The following compound of Example 409 was synthesized by carrying outreaction according to the method described in Example 385, except forusing thecis-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dioneobtained in Example 326, (d) and the 4-methyl-1H-indazol-5-ol obtainedin Example 402, as starting materials.

EXAMPLE 409 trans-3-[(4-Methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 156–160° C.

The following compound of Example 410 was synthesized by carrying outreactions according to the methods described in Example 385 and Example327, except for using thetrans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 323, (a) and the 4-methyl-1H-indazol-5-ol obtained in Example402, as starting materials.

EXAMPLE 410 cis-4-[(4-Methyl-1H-indazol-5-yl)oxy]cyclohexanaminehydrochloride

¹H-NMR (DMSO-d₆) δ; 1.64 (2H, m), 1.75 (4H, m), 1.92 (2H, m), 2.44 (3H,s), 3.09 (1H, m), 4.44 (1H, m), 7.13 (1H, d, J=9.0 Hz), 7.27 (1H, d,J=9.0 Hz), 7.91 (3H, brs), 8.02 (1H, s).

The following compound of Example 411 was synthesized by carrying outreaction according to the method described in Example 385, except forusing thetrans-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dioneobtained in Example 385, (b) and the 4-methyl-1H-indazol-5-ol obtainedin Example 402, as starting materials.

EXAMPLE 411 cis-3-[(4-Methyl-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 0.90 (1H, m), 1.04–1.29 (3H, m), 1.46 (2H, s), 1.66(2H, m), 1.98 (1H, m), 2.09 (1H, m), 2.50 (1H, m), 3.99 (1H, m), 7.11(1H, d, J=9.0 Hz), 7.25 (1H, d, J=9.0 Hz), 8.00 (1H, s), 12.86 (1H, s).

The following compounds of Examples 412 to 415 were synthesized bycarrying out reaction according to the method described in Example 140,except for using thetrans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained inExample 408, as a starting material.

EXAMPLE 412trans-N,N-dimethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=274 (M+1)

EXAMPLE 413trans-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylamine

MS: m/z=288 (M+1)

EXAMPLE 414trans-N-isopropyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=288 (M+1)

EXAMPLE 415trans-N-cyclopentyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=314 (M+1)

The following compound of Example 416 was synthesized by carrying outreaction according to the method described in Example 390, except forusing the trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 408, as a starting material.

EXAMPLE 416trans-N-butyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

MS: m/z=302 (M+1)

The following compound of Example 417 was synthesized by carrying outreaction according to the method described in Example 391, except forusing the trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 408, as a starting material.

EXAMPLE 417trans-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

MS: m/z=288 (M+1)

The following compound of Example 418 was synthesized by carrying outreaction according to the method described in Example 399, except forusing the trans-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamideobtained in Example 417, as a starting material.

EXAMPLE 418trans-N-ethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 150–151° C.

EXAMPLE 419 Synthesis oftrans-N,N-diethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamineSynthesis oftrans-N-ethyl-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

The title compound was synthesized by carrying out reaction according tothe method described in Example 391, except for using thetrans-N-ethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtainedin Example 418, as a starting material.

(b) Synthesis oftrans-N,N-diethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Except for usingtrans-N-ethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine as astarting material,trans-N,N-diethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine wasobtained by carrying out reaction according to the method described inExample 399.

MS: m/z=302 (M+1)

The following compound of Example 420 was synthesized by carrying outreaction according to the method described in Example 140, except forusing the trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 409, as a starting material.

EXAMPLE 420trans-N-isopropyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=287 (M+1)

The following compound of Example 421 was synthesized by carrying outreaction according to the method described in Example 390, except forusing the trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 409, as a starting material.

EXAMPLE 421trans-N,N-diethyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

MS: m/z=302 (M+1)

EXAMPLE 422 Synthesis of 4-methyl-5-(piperidin-3-yloxy)-1H-indazole (a)Synthesis of t-butyl3-[(4-methyl-1H-indazol-5-yl)oxy]piperidine-1-carboxylate

A solution of dibenzyl dicarboxylate (10.1 g, 33.9 mmol) intetrahydrofuran (50 ml) was added dropwise to a mixture of the5-hydroxy-4-methyl-1H-indazole (4.17 g, 28.1 mmol) obtained in Example402, t-butyl 3-hydroxypiperidine-1-carboxylate (5.62 g, 27.9 mmol) andtetrahydrofuran (100 ml) under ice-cooling. After 30 minutes, themixture thus obtained was warmed up to room temperature and stirred for16 hours. The reaction mixture was concentrated and then a 1N-aqueoussodium hydroxide solution (250 ml) was added thereto, followed byextraction with chloroform (150 ml) (three times). The organic layer waswashed with a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate=3/1 to 2/1) to obtain acrude product t-butyl3-[(4-methyl-1H-indazol-5-yl)oxy]piperidine-1-carboxylate (a mixturewith t-butyl 3-hydroxypiperidine-1-carboxylate, 3.46 g).

(b) Synthesis of 4-methyl-5-(piperidin-3-yloxy)-1H-indazole

A 4N-hydrochloric acid/dioxane solution (15 ml) was added dropwise to asolution of the crude product t-butyl3-[(4-methyl-1H-indazol-5-yl)oxy]piperidine-1-carboxylate (3.46 g) inmethanol (15 ml), and the resulting mixture was stirred at roomtemperature for 1 hour. The solvent was distilled off, and to thehydrochloride thus obtained was added a 1N-aqueous sodium hydroxidesolution (100 ml), followed by extraction with ethyl acetate (60 ml)(twice). The extract solution was dried over magnesium sulfate anddistilled under reduced pressure to remove the solvent, and theresulting residue was purified by a silica gel column chromatography(eluent:chloroform/methanol=20/1˜chloroform/methanol/triethylamine=20/1/1) toobtain 4-methyl-5-(piperidin-3-yloxy)-1H-indazole (1.51 g, two steps23%).

Melting point: 183–185° C.

EXAMPLE 423 Synthesis of4-methyl-5-[(1-methylpiperidin-3-yl)oxy]-1H-indazole

Acetic acid (0.060 ml) was added to a methanolic solution (1.0 ml) ofthe 4-methyl-5-(piperidin-3-yloxy)-1H-indazole (46 mg, 0.20 mmol)obtained in Example 422, followed by adding thereto paraformaldehyde (30mg, 1.0 mmol), and the resulting mixture was stirred at room temperaturefor 2 hours. Then, a solution of sodium cyanoborohydride (63 mg, 1.0mmol) in methanol (1.0 ml) was added thereto and the resulting mixturewas stirred at room temperature for 18 hours. After a 1N-aqueous sodiumhydroxide solution (0.8 ml) was added to the reaction solution, thesolvent was distilled off under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate/triethylamine=5/15/1) to obtain4-methyl-5-[(1-methylpiperidin-3-yl)oxy]-1H-indazole (34 mg, 70%).

MS: m/z=246 (M+1)

The following compounds of Example 424 to Example 427 were synthesizedaccording to the process described in Example 423.

EXAMPLE 424 4-Methyl-5-[(1-propylpiperidin-3-yl)oxy]-1H-indazole

MS: m/z=274 (M+1)

EXAMPLE 425 5-[(1-Isopropylpiperidin-3-yl)oxy]-4-methyl-1H-indazole

MS: m/z=274 (M+1)

EXAMPLE 426 5-[(1-Cyclopentylpiperidin-3-yl)oxy]-4-methyl-1H-indazole

¹H-NMR (DMSO-d₆) δ; 0.91 (1H, d, J=6.6 Hz), 1.30–1.50 (2H, m), 1.67–1.78(1H, m), 1.90-1.99 (1H, m), 2.10–2.22 (2H, m), 2.38 (3H, s), 2.53–2.61(1H, m), 2.61–2.71 (1H, m), 2.82–2.90 (1H, m), 4.02–4.13 (3H, m), 7.10(2H, d, J=9.0 Hz), (1H, d, J=9.0 Hz), 8.00 (1H, s), 12.86 (1H, s).

EXAMPLE 427 5-[(1-Cyclobutylpiperidin-3-yl)oxy]-4-methyl-1H-indazole

MS: m/z=286 (M+1)

The following compounds of Example 428 to Example 432 were synthesizedaccording to the process described in Example 423, except for using the5-(piperidin-3-yloxy)-1H-indazole obtained in Example 377, as a startingmaterial.

EXAMPLE 428 5-[(1-Methylpiperidin-3-yl)oxy]-1H-indazole

MS: m/z=232 (M+1)

EXAMPLE 429 5-[(1-Propylpiperidin-3-yl)oxy]-1H-indazole

MS: m/z=260 (M+1)

EXAMPLE 430 5-[(1-Isopropylpiperidin-3-yl)oxy]-1H-indazole

¹H-NMR (DMSO-d₆) δ; 0.91 (6H, d, J=6.6 Hz), 1.20–1.37 (1H, m), 1.37–1.57(1H, m), 1.64–1.76 (1H, m), 1.96–2.20 (3H, m), 2.58–2.67 (1H, m),2.67–2.76 (1H, m), 2.90–3.01 (1H, m), 4.20–4.30 (1H, m), 6.97 (1H, dd,J=2.1, 8.8 Hz), 7.20 (1H, d, J=1.9 Hz), 7.41 (1H, d, J=9.0 Hz), 7.91(1H, s), 12.87 (1H, s).

EXAMPLE 431 5-[(1-Cyclopentylpiperidin-3-yl)oxy]-1H-indazole

MS: m/z=286 (M+1)

EXAMPLE 432 5-[(1-Cyclobutylpiperidin-3-yl)oxy]-1H-indazole

MS: m/z=272 (M+1)

The following compounds of Example 433 to Example 436 were synthesizedaccording to the process described in Example 423, except for using the4-methyl-5-(piperidin-4-yloxy)-1H-indazole obtained in Example 404, as astarting material.

EXAMPLE 433 4-Methyl-5-[(1-methylpiperidin-4-yl)oxy]-1H-indazole

MS: m/z=246 (M+1)

EXAMPLE 434 4-Methyl-5-[(1-propylpiperidin-4-yl)oxy]-1H-indazole

MS: m/z=274 (M+1)

EXAMPLE 435 5-[(1-Isopropylpiperidin-4-yl)oxy]-4-methyl-1H-indazole

Melting point: 134–136° C.

EXAMPLE 436 5-[(1-Cyclopentylpiperidin-4-yl)oxy]-4-methyl-1H-indazole

Melting point: 140–143° C.

The following compounds of Example 437 to Example 440 were synthesizedaccording to the process described in Example 423, except for using the5-(azepan-4-yloxy)-1H-indazole obtained in Example 379, as a startingmaterial.

EXAMPLE 437 5-[(1-Methylazepan-4-yl)oxy]-1H-indazole

MS: m/z=246 (M+1)

EXAMPLE 438 5-[(1-Propylazepan-4-yl)oxy]-1H-indazole

MS: m/z=274 (M+1)

EXAMPLE 439 5-[(1-Isopropylazepan-4-yl)oxy]-1H-indazole

MS: m/z=274 (M+1)

EXAMPLE 440 5-[(1-Cyclopentylazepan-4-yl)oxy]-1H-indazole

Melting point: 138–140° C.

The following compounds of Example 441 to Example 444 were synthesizedaccording to the process described in Example 423, except for using the5-(azepin-4-yloxy)-4-methyl-1H-indazole obtained in Example 407, as astarting material.

EXAMPLE 441 4-Methyl-5-[(1-methylazepan-4-yl)oxy]-4-methyl-1H-indazole

MS: m/z=260 (M+1)

EXAMPLE 442 4-Methyl-5-[(1-propylazepan-4-yl)oxy]-4-methyl-1H-indazole

MS: m/z=288 (M+1)

EXAMPLE 443 5-[(1-Isopropylazepan-4-yl)oxy]-4-methyl-1H-indazole

MS: m/z=288 (M+1)

EXAMPLE 444 5-[(1-Cyclopentylazepan-4-yl)oxy]-4-methyl-1H-indazole

Melting point: 126–131° C.

The following compounds of Example 445 to Example 449 were synthesizedaccording to the process described in Example 423, except for using thecis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example410, as a starting material.

EXAMPLE 445cis-N,N-dimethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=274 (M+1)

EXAMPLE 446cis-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylamine

MS: m/z=288 (M+1)

EXAMPLE 447 cis-N-butyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=302 (M+1)

EXAMPLE 448cis-N-isopropyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 166–168° C.

EXAMPLE 449cis-N-cyclopentyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 153–155° C.

EXAMPLE 450 Synthesis of 2-[3-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol

A mixture of the 5-(piperidin-3-yloxy)-1H-indazole (43 mg, 0.20 mmol)obtained in Example 377, 2-iodoethanol (84 mg, 0.49 mmol), potassiumcarbonate (70 mg, 0.50 mmol) and N,N-dimethylformamide (1 ml) wasstirred at room temperature for 24 hours. The precipitate was removed byfiltration and the solvent was distilled off as an azeotrope withtoluene. The residue oil was purified by a silica gel columnchromatography (eluent: ethyl acetate/triethylamine/ethanol=20/1/1) toobtain 2-[3-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol (17 mg, 32%).

MS: m/z=261 (M+1)

The following compound of Example 451 was synthesized according to theprocess described in Example 450, except for using the4-methyl-5-(piperidin-3-yloxy)-1H-indazole obtained in Example 422, as astarting material.

EXAMPLE 451 2-{3-[(4-Methyl-1H-indazol-5-yl)oxy]piperidin-1-yl}ethanol

MS: m/z=276 (M+1)

The following compound of Example 452 was synthesized according to theprocess described in Example 450, except for using the4-methyl-5-(piperidin-4-yloxy)-1H-indazole obtained in Example 404, as astarting material.

EXAMPLE 452 2-{4-[(4-Methyl-1H-indazol-5-yl)oxy]piperidin-1-yl}ethanol

MS: m/z=276 (M+1)

The following compound of Example 453 was synthesized according to theprocess described in Example 450, except for using the5-(azepan-4-yloxy)-1H-indazole obtained in Example 379, as a startingmaterial.

EXAMPLE 453 2-[4-(1H-indazol-5-yloxy)azepan-1-yl]ethanol

MS: m/z=276 (M+1)

The following compound of Example 454 was synthesized according to theprocess described in Example 450, except for using the5-(azepin-4-yloxy)-4-methyl-1H-indazole obtained in Example 407, as astarting material.

EXAMPLE 454 2-{4-[(4-Methyl-1H-indazol-5-yl)oxy]azepan-1-yl}ethanol

¹H-NMR (DMSO-d₆) δ; 1.30–1.60 (1H, m), 1.65–1.85 (3H, m), 1.85–2.06 (2H,m), 2.36 (3H, s), 2.62 (2H, t, J=5.9 Hz), 2.65–2.77 (1H, m), 3.44 (2H,t, J=6.4 Hz), 4.22–4.42 (2H, m), 7.08 (1H, d, J=8.8 Hz), 7.27 (1H, d,J=8.8 Hz), 7.99 (1H, s), 12.85 (1H, s).

EXAMPLE 455 Synthesis of5-[(1-acetylpiperidin-3-yl)oxy]-4-methyl-1H-indazole

Triethylamine (0.14 ml, 1.0 mmol) was added to a mixture of the4-methyl-5-(piperidin-3-yloxy)-1H-indazole (92 mg, 0.40 mmol) obtainedin Example 422, acetic acid (24 mg, 0.40 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (77 mg,0.40 mmol), 1-hydroxybenzo-triazole (54 mg, 0.40 mmol) andN,N-dimethylformamide (1.5 ml), and the resulting mixture was stirred atroom temperature for 19 hours. The mixture was diluted with a mixedsolution of ethyl acetate (10 ml)/toluene (10 ml) and washed with waterand then a saturated aqueous sodium hydrogencarbonate solution. Themixture washed was dried over potassium carbonate and then concentratedto dryness to obtain5-[(1-acetylpiperidin-3-yl)oxy]-4-methyl-1H-indazole (84 mg, 76%).

¹H-NMR (DMSO-d₆) δ; 1.30–1.55 (1H, m), 1.60–2.05 (6H, m), 2.34 (3H, s),3.10–4.46 (5H, m), 7.10–7.20 (1H, m), 7.29 (1H, t, J=7.9 Hz), 8.01 (1H,s), 12.88 (1H, s).

The following compound of Example 456 was synthesized according to theprocess described in Example 455, except for using the5-(piperidin-3-yloxy)-1H-indazole obtained in Example 377, as a startingmaterial.

EXAMPLE 456 5-[(1-Acetylpiperidin-3-yl)oxy]-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.30–1.58 (1H, m), 1.58–2.07 (6H, m), 2.34 (3H, s),3.13–4.52 (5H, m), 7.29 (1H, dt, J=2.6, 9.0 Hz), 7.22–7.29 (1H, m),7.39–7.47 (1H, m), 8.04 (1H, s), 12.91 (1H, s).

The following compound of Example 457 was synthesized according to theprocess described in Example 455, except for using the4-methyl-5-(piperidin-4-yloxy)-1H-indazole obtained in Example 404, as astarting material.

EXAMPLE 457 5-[(1-Acetylpiperidin-4-yl)oxy]-4-methyl-1H-indazole

Melting point: 161–163° C.

The following compound of Example 458 was synthesized according to theprocess described in Example 455, except for using the5-(azepan-4-yloxy)-1H-indazole obtained in Example 379, as a startingmaterial.

EXAMPLE 458 5-[(1-Acetylazepan-4-yl)oxy]-1H-indazole

¹H-NMR (CDCl₃) δ; 1.60–1.80 (3H,m), 1.80–2.40 (7H,m), 3.44–3.87 (3H,m),4.43–4.56 (1H,m), 7.02–7.10 (1H,m), 7.10–7.22 (2H,m), 7.97 (1H,s).

The following compound of Example 459 was synthesized according to theprocess described in Example 455, except for using the5-(azepin-4-yloxy)-4-methyl-1H-indazole obtained in Example 407, as astarting material.

EXAMPLE 459 5-[(1-Acetylazepan-4-yl)oxy]-4-methyl-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.70–2.10 (10H, m), 2.37 (3H, s), 3.38–3.53 (3H, m),4.26–4.42 (1H, m), 7.07–7.19 (1H, m), 7.19–7.31 (1H, m), 8.00 (1H, s),12.86 (1H, s).

The following compound of Example 460 was synthesized according to theprocess described in Example 455, except for using thecis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example410, as a starting material.

EXAMPLE 460 cis-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

¹H-NMR (DMSO-d₆) δ; 1.50–1.70 (6H, m), 1.70–1.94 (5H, m), 2.43 (3H, s),3.63 (1H, s), 4.35 (1H, s), 7.10 (1H, d, J=9.2 Hz), 7.27 (1H, d, J=8.8Hz), 7.94 (1H, s), 8.00 (1H, s), 12.85 (1H, s).

EXAMPLE 461 Synthesis of5-[(1-ethylpiperidin-3-yl)oxy]-4-methyl-1H-indazole

A mixture of the 5-[(1-acetylpiperidin-3-yl)oxy]-4-methyl-1H-indazole(55.1 mg, 0.202 mmol) obtained in Example 455, lithium aluminum hydride(40 mg, 1.1 mmol) and tetrahydrofuran (2 ml) was stirred at 80° C. for2.5 hours. The reaction mixture was ice-cooled, followed by addingthereto water (0.04 ml), a 2N-aqueous sodium hydroxide solution (0.08ml) and water (0.12 ml) in that order. The precipitate was removed byfiltration and the solvent was distilled off. Thereafter, the residueoil was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate/triethylamine=5/15/1) to obtain5-[(1-ethylpiperidin-3-yl)oxy]-4-methyl-1H-indazole (14 mg, 28%).

MS: m/z=260 (M+1)

The following compound of Example 462 was synthesized according to theprocess described in Example 461, except for using the5-[(1-acetylpiperidin-3-yl)oxy]-1H-indazole obtained in Example 456, asa starting material.

EXAMPLE 462 5-[(1-Ethylpiperidin-3-yl)oxy]-1H-indazole

¹H-NMR (DMSO-d₆) δ; 0.89 (3H, t, J=7.2 Hz), 1.26–1.48 (2H, m), 1.62–1.72(1H, m), 1.84–2.05 (3H, m), 2.27 (2H, q, J=4.2 Hz), 2.33 (3H, s),2.50–2.60 (1H, m), 2.78–2.87 (1H, m), 4.00–4.10 (1H, m), 7.08 (1H, d,J=8.8 Hz), 7.23 (1H, d, J=9.0 Hz), 7.96 (1H, s), 12.83 (1H, s)

The following compound of Example 463 was synthesized according to theprocess described in Example 461, except for using the5-[(1-acetylpiperidin-4-yl)oxy]-4-methyl-1H-indazole obtained in Example457, as a starting material.

EXAMPLE 463 5-[(1-Ethylpiperidin-4-yl)oxy]-4-methyl-1H-indazole

¹H-NMR (DMSO-d₆) δ; 0.98 (3H, t, J=7.1 Hz), 1.56–1.70 (2H, m), 1.81–1.92(2H, m), 2.03–2.16 (2H, m), 2.30 (2H, q, J=4.2 Hz), 2.39 (3H, s),2.62–2.72 (2H, m), 4.08–4.18 (1H, m), 7.11 (1H, d, J=8.8 Hz), 7.27 (1H,d, J=9.2 Hz), 8.00 (1H, s), 12.86 (1H, s).

The following compound of Example 464 was synthesized according to theprocess described in Example 461, except for using the5-[(1-acetylazepan-4-yl)oxy]-1H-indazole obtained in Example 458, as astarting material.

EXAMPLE 464 5-[(1-Ethylazepan-4-yl)oxy]-1H-indazole

MS: m/z=260 (M+1)

The following compound of Example 465 was synthesized according to theprocess described in Example 461, except for using the5-[(1-acetylazepan-4-yl)oxy]-4-methyl-1H-indazole obtained in Example459, as a starting material.

EXAMPLE 465 5-[(1-Ethylazepan-4-yl)oxy]-4-methyl-1H-indazole

¹H-NMR (DMSO-d₆) δ; 0.96 (3H, t, J=7.1 Hz), 1.40–1.57 (1H, m), 1.68–1.85(3H, m), 1.85–2.04 (2H, m), 2.36 (3H, s), 2.40–2.68 (4H, m), 4.34–4.41(1H, m), 7.08 (1H, d, J=9.1 Hz), 7.27 (1H, d, J=9.5 Hz), 7.99 (1H, s),12.85 (1H, s).

The following compound of Example 466 was synthesized according to theprocess described in Example 461, except for using thecis-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide obtained inExample 460, as a starting material.

EXAMPLE 466 cis-N-ethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=274 (M+1)

EXAMPLE 467 Synthesis of 4-methoxy-1H-indazol-5-yl methanesulfonate (a)Synthesis of 2-methoxy-1-(methoxymethoxy)-4-nitrobenzene

N,N-diisopropylethylamine (1.24 ml, 7.09 mmol), chloromethoxymethylether (0.494 ml, 6.50 mmol) and tetrabutylammonium bromide (218 mg,0.591 mmol) were added to a solution of 2-methoxy-4-nitrophenol (1.0 g,5.91 mmol) in dichloromethane (20 ml) at 0° C. After 1 hour, the mixturethus obtained was warmed up to room temperature. After 15 hours, themixture was poured into water (50 ml) and extracted with chloroform (50ml×2), and the organic layer was dried over anhydrous magnesium sulfate.The organic layer dried was concentrated under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate) to obtain2-methoxy-1-(methoxymethoxy)-4-nitrobenzene (1.26 g, 100%).

(b) Synthesis ofN-[3-methoxy-4-(methoxymethoxy)phenyl]-2,2-dimethylpropanamide

To a solution of 2-methoxy-1-(methoxymethoxy)-4-nitrobenzene (1.2 g,5.63 mmol) in ethyl acetate (30 ml) was added 10%-Pd/C (120 mg) at roomtemperature, and reaction was carried out under a hydrogen atmosphere.After 30 minutes, the mixture thus obtained was filtered by the use ofCelite and the filtrate was concentrated under reduced pressure. To asolution of the resulting residue in ethyl acetate (30 ml) were addedpyridine (0.546 ml, 6.75 mmol) and pivaloyl chloride (0.763 ml, 6.19mmol) at 0° C., and the resulting mixture was warmed up to roomtemperature. After 15 hours, a saturated aqueous sodiumhydrogencarbonate solution was added to the reaction solution and theresulting mixture was poured into water (100 ml) and extracted withethyl acetate (50 ml×2), and the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtainN-[3-methoxy-4-(methoxymethoxy)phenyl]-2,2-dimethylpropanamide (1.48 g,98%).

(c) Synthesis ofN-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamide

To a solution ofN-[3-methoxy-4-(methoxymethoxy)phenyl]-2,2-dimethylpropanamide (500 mg,1.87 mmol) in tetrahydrofuran (10 ml) was added dropwise1.59M-n-butyllithium (2.94 ml, 4.68 mmol) at −15° C., and the resultingmixture was slowly warmed up to 0° C. After 2 hours, a solution ofmethyl iodide (0.175 ml, 2.81 mmol) in tetrahydrofuran (0.5 ml) wasadded dropwise thereto. After 1 hour, the resulting mixture was warmedup to room temperature. After 14 hours, the reaction solution was pouredinto water (50 ml) and extracted with ethyl acetate (30 ml×3), and theorganic layer was dried over anhydrous magnesium sulfate. The organiclayer dried was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate) to obtainN-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamide(424 mg, 81%).

(d) Synthesis of4-[(2,2-dimethylpropanoyl)amino]-2-methoxy-3-methylphenylMethanesulfonate

A 6N aqueous hydrochloric acid solution (0.355 ml, 2.13 mmol) was addeddropwise to a solution ofN-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamide(300 mg, 1.07 mmol) in methanol (3 ml) at room temperature. After 18hours, the reaction solution was poured into water (30 ml) and extractedwith ethyl acetate (30 ml×2), and the ethyl acetate layer was washedwith a saturated aqueous sodium chloride solution and then dried overanhydrous magnesium sulfate. The ethyl acetate layer dried wasconcentrated under reduced pressure, and to a solution of the resultingresidue in pyridine (3 ml) was added methanesulfonyl chloride (0.091 ml,1.17 mmol) at 0° C. The resulting mixture was heated to 60° C. After 2.5hours, the reaction solution was concentrated under reduced pressure andthe resulting residue was poured into water (50 ml) and extracted withethyl acetate (30 ml×2). The extract solution was dried over anhydrousmagnesium sulfate. The extract solution dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain4-[(2,2-dimethylpropanoyl)amino]-2-methoxy-3-methylphenylmethanesulfonate (338 mg, 100%).

(e) Synthesis of 4-(acetylamino)-2-methoxy-3-methylphenylmethanesulfonate

A 20%-aqueous sulfuric acid solution (4 ml) was added dropwise to asolution of 4-[(2,2-dimethylpropanoyl)amino]-2-methoxy-3-methylphenylmethanesulfonate (223 mg, 0.707 mmol) in n-butanol (2 ml) at roomtemperature, and the resulting mixture was heated to 100° C. After 14hours, the reaction solution was poured onto ice (50 ml) and adjusted topH 11 with an aqueous sodium hydroxide solution. The resulting mixturewas extracted with ethyl acetate (50 ml×3) and the organic layer wasdried over anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure, and to a solution of the resultingresidue in ethyl acetate (5 ml) were added pyridine (0.069 ml, 0.848mmol) and acetic anhydride (0.073 ml, 0.778 mmol) at room temperature.The resulting mixture was heated to 60° C. After 2 hours, the reactionsolution was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate→chloroform/ethyl acetate) to obtain4-(acetylamino)-2-methoxy-3-methylphenyl methanesulfonate (154 mg, 79%).

(f) Synthesis of 1-acetyl-4-methoxy-1H-indazol-5-yl methanesulfonate

Acetic anhydride (155?1, 1.65 mmol), tetrabutylammonium bromide (8.8 mg,0.0274 mmol), potassium acetate (108 mg, 1.10 mmol) and isoamyl nitrite(0.096 ml, 0.274 mmol) were added to a solution of4-(acetylamino)-2-methoxy-3-methylphenyl methanesulfonate (150 mg, 0.549mmol) in ethyl acetate (1.5 ml) at room temperature. After 8 hours,isoamyl nitrite (0.037 ml, 0.713 mmol) was further added thereto. Afteranother 2 hours, the mixture thus obtained was poured into water (20 ml)and extracted with ethyl acetate (20 ml×2), and the organic layer wasdried over anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain 1-acetyl-4-methoxy-1H-indazol-5-yl methanesulfonate(110 mg, 70%).

(g) Synthesis of 4-methoxy-1H-indazol-5-yl methanesulfonate

A 2M-aqueous lithium hydroxide solution (0.352 ml, 0.704 mmol) was addedto a solution of 1-acetyl-4-methoxy-1H-indazol-5-yl methanesulfonate(100 mg, 0.352 mmol) in a mixture of tetrahydrofuran (1.0 ml) andmethanol (1.0 ml) at room temperature. After 1 hour, the resultingmixture was poured into water (10 ml) and extracted with ethyl acetate(20 ml×2), and the organic layer was dried over anhydrous magnesiumsulfate. The organic layer dried was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtain4-methoxy-1H-indazol-5-yl methanesulfonate (80 mg, 94%).

Melting point: 130–131° C.

EXAMPLE 468 Synthesis of 4-chloro-1H-indazol-5-ol

To a solution of the 1H-indazol-5-ol (1.60 g, 0.0119 mol) obtained inReference Example 4 in tetrahydrofuran (50 ml) was addedN-chlorosuccinimide (1.59 g, 0.0119 mol) at room temperature. After 1hour, the mixture thus obtained was heated to 40° C., and after another2 hour, the mixture was heated to 50° C. After 5 hours, the reactionsolution was poured into water (100 ml) and extracted with ethyl acetate(100 ml×3). The organic layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure, and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain 4-chloro-1H-indazol-5-ol (1.7365 g, 86%).

¹H-NMR (DMSO-d₆) δ; 7.09 (1H, d, J=8.8 Hz), 7.33 (1H, d, J=8.8 Hz), 7.90(1H, s), 9.71 (1H, s), 13.10 (1H, s).

EXAMPLE 469 Synthesis of 4-methoxy-1H-indazol-5-ol (a) Synthesis of4-methoxy-1H-indazol-5-yl 2-nitrobenzenesulfonate

Title compound was synthesized by carrying out reaction according to themethod described in Example 467, except for using theN-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamidesynthesized in Example 467, (c), as a starting material.

(b) Synthesis of 4-methoxy-1H-indazol-5-ol

Cesium carbonate (45 mg, 0.137 mmol) and thiophenol (24 ml, 0.229 mmol)were added to a solution of 4-methoxy-1H-indazol-5-yl2-nitrobenzenesulfonate (40 mg, 0.115 mmol) in N,N-dimethylformamide (1ml) at 0° C. After 30 minutes, the reaction solution was poured intowater (20 ml) and extracted with ethyl acetate (20 ml×2). The organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure, and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain4-methoxy-1H-indazol-5-ol (19 mg, 100%).

¹H-NMR (DMSO-d₆) δ; 3.97 (3H, s), 6.95 (1H, d, J=8.7 Hz), 7.00 (1H, d,J=8.7 Hz), 8.01 (1H, s), 8.57 (1H, s), 12.81 (1H, s).

The following compound of Example 470 was synthesized by carrying outreaction according to the method described in Example 385, except forusing the 4-chloro-1H-indazol-5-ol synthesized in Example 468, as astarting material.

EXAMPLE 470 trans-3-[(4-Chloro-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 142–144° C.

The following compound of Example 471 was synthesized by carrying outreaction according to the method described in Example 470, except forusing the 4-chloro-1H-indazol-5-ol synthesized in Example 468, as astarting material.

EXAMPLE 471 cis-3-[(4-Chloro-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 0.92 (1H, m), 1.17 (1H, m), 1.23 (2H, m), 1.70 (2H,m), 1.96 (1H, m), 2.10 (1H, m), 2.53 (1H, m), 4.16 (1H, m), 7.30 (1H, d,J=9.0 Hz), 7.45 (1H, d, J=9.0 Hz), 8.01 (1H, s).

The following compound of Example 472 was synthesized by carrying outreaction according to the method described in Example 470, except forusing the 4-chloro-1H-indazol-5-ol synthesized in Example 468, as astarting material.

EXAMPLE 472 trans-4-[(4-chloro-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 1.13 (2H, m), 1.42 (2H, m), 1.75 (2H, m), 1.98 (2H,m), 2.62 (1H, m), 4.17 (1H, m), 7.30 (1H, d, J=9.0 Hz), 7.44 (1H, dd,J=0.8, 9.0 Hz), 8.01 (1H, d, J=0.8 Hz).

EXAMPLE 473 Synthesis of 5-methoxy-4-(trifluoromethyl)-1H-indazole (a)Synthesis of 4-methoxy-3-(trifluoromethyl)aniline

To a solution of 2-methoxy-5-nitrobenzotrifluoride (5.08 g, 23.0 mmol)in methanol (200 ml) was added 10% Pd—C (containing 50% water, 250 mg),and the resulting mixture was stirred for 3.5 hours under a hydrogenatmosphere at room temperature and atmospheric pressure whilemaintaining the temperature. The mixture was filtered by the use ofCelite and the filtrate was concentrated to dryness under reducedpressure to obtain 4-methoxy-3-(trifluoromethyl)aniline (4.67 g, 100%).

MS: m/z=192 (M+1)

(b) Synthesis ofN-[4-methoxy-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide

Triethylamine (6.24 ml, 44.8 mmol) was added to a solution of4-methoxy-3-(trifluoromethyl)aniline (4.29 g, 22.4 mmol) indichloromethane (45.0 ml), and the resulting mixture was ice-cooled,followed by adding dropwise thereto pivaloyl chloride (2.84 g, 23.5mmol) at 0 to 5° C. The resulting mixture was warmed up to roomtemperature and stirred for 1 hour while maintaining the temperature.The mixture was partitioned by the use of a 5%-aqueous sodiumhydrogencarbonate solution and ethyl acetate, and the organic layer waswashed with a 5% aqueous sodium chloride solution, dried over anhydroussodium sulfate, and then filtered. The filtrate was concentrated underreduced pressure to obtainN-[4-methoxy-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (6.16 g,100%).

¹H-NMR (CDCl₃) δ; 1.32 9H, s), 3.89 (3H, s), 6.96 (1H, d, J=8.9 Hz),7.31 (1H, br s), 7.63 (1H, d, J=2.8 Hz), 7.76 (1H, dd, J=2.8, 8.9 Hz).

(c) Synthesis ofN-[4-methoxy-2-methyl-3-(trifluoromethyl)-phenyl]-2,2-dimethylpropanamide

A solution ofN-[4-methoxy-3-(trifluoromethyl)-phenyl]-2,2-dimethylpropanamide (5.90g, 21.4 mmol) in tetrahydrofuran (70.0 ml) was cooled to −10 to −15° C.,and then a 1.57M n-butyllithium/hexane solution (33.5 ml, 52.5 mmol) wasadded dropwise thereto over a period of 25 minutes while maintaining theinternal temperature at 0° C. or lower. The resulting mixture was slowlywarmed up to 20° C. and stirred for 3 hours while maintaining thetemperature. The resulting suspension was cooled to −35 to −40° C., andthen iodomethane (1.53 ml, 24.6 mmol) was added dropwise thereto over aperiod of 15 minutes. The resulting mixture was slowly warmed up to −5to 0° C. and stirred for 1.5 hours while maintaining the temperature.The mixture was partitioned and extracted with water and ethyl acetate,and the organic phase was washed with a 5% aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, and then filtered. Thefiltrate was concentrated under reduced pressure to obtain a crudeproduct (6.23 g). The crude product was purified by a silica gel columnchromatography (eluent: hexane/diisopropyl ether=1/1) to obtainN-[4-methoxy-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide(3.20 g, 50%).

¹H-NMR (CDCl₃) δ; 1.35 (9H, s), 2.31 (3H, q, J=2.9 Hz), 3.86 (3H, s),6.87 (1H, d, J=9.0 Hz), 7.08 (1H, brs), 7.57 (1H, d, J=9.0 Hz).

(d) Synthesis of 4-methoxy-2-methyl-3-(trifluoromethyl)-aniline

N-[4-methoxy-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide(3.15 g, 10.9 mmol) and potassium hydroxide (3.20 g, 57.1 mmol) wereslowly heated to 160° C. in ethylene glycol (31.0 ml) and stirred for 20hours while maintaining the temperature. The reaction solution wasportioned and extracted with water and chloroform, and the organic phasewas extracted with a 1N aqueous hydrochloric acid solution to obtain anaqueous phase. This aqueous phase was made basic with a 2N aqueoussodium hydroxide solution and extracted three times with chloroform. Thecombined organic phase was dried over anhydrous magnesium sulfate andfiltered, and the filtrate was concentrated under reduced pressure toobtain 4-methoxy-2-methyl-3-(trifluoromethyl)-aniline (1.10 g, 49%).

¹H-NMR (CDCl₃) δ; 2.25 (3H, q, J=2.4 Hz), 3.79 (3H, s), 6.76 (1H, d,J=8.8 Hz), 6.82 (1H, d, J=8.8 Hz).

(e) Synthesis of 1-acetyl-5-methoxy-4-(trifluoromethyl)-1H-indazole

Acetic anhydride (377 μl, 4.00 mmol) was added dropwise to a solution of4-methoxy-2-methyl-3-(trifluoromethyl)aniline (513 mg, 2.50 mmol) inethyl acetate (3.0 ml) at room temperature. Ethyl acetate (4.5 ml) wasadded to the solidified reaction solution and the resulting mixture wasslowly heated to 65° C. and stirred for 15 minutes while maintaining thetemperature. The resulting reaction solution was cooled to roomtemperature, followed by adding thereto acetic anhydride (708 μl, 7.50mmol), tetrabutylammonium bromide (40.3 mg, 0.125 mmol), potassiumacetate (491 mg, 5.00 mmol) and isopentyl nitrite (437 μl, 3.25 mmol) inthat order at room temperature. The resulting mixture was slowly heatedto 65° C. and stirred for 6 hours while maintaining the temperature.After cooling, the mixture was partitioned and extracted with water andethyl acetate, and the organic layer was washed with a 5% aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, and thenfiltered. The filtrate was concentrated under reduced pressure to obtaina crude product (800 mg). The crude product was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate=9/1 to 6/1) toobtain 1-acetyl-5-methoxy-4-(trifluoromethyl)-1H-indazole (496 mg, 77%).

¹H-NMR (CDCl₃) δ; 2.79 (3H, s), 4.00 3H, s), 7.33 (1H, d, J=9.2 Hz),8.24 (1H, m), 8.63 (1H, d, J=9.2 Hz).

(f) Synthesis of 5-methoxy-4-(trifluoromethyl)-1H-indazole

A 6N-aqueous sodium hydroxide solution (3.8 ml, 23 mmol) was addeddropwise to a solution of1-acetyl-5-methoxy-4-(trifluoromethyl)-1H-indazole (493 mg, 1.91 mmol)in a mixture of methanol (3.8 ml) and tetrahydrofuran (3.8 ml) at roomtemperature and stirred at room temperature for 5 hours whilemaintaining the temperature. The resulting reaction solution wasadjusted to pH 8 to 9 by dropwise addition of 12N-aqueous hydrochloricacid solution (1.5 ml) and then a 1N aqueous hydrochloric acid solution(about 2 ml), and distilled under reduced pressure to remove the organicsolvent. The white precipitate formed was diluted with water, filtered,washed with water, and then dried under reduced pressure to obtain5-methoxy-4-(trifluoromethyl)-1H-indazole (400 mg, 97%).

¹H-NMR (CDCl₃) δ; 3.98 (3H, s), 7.27 (1H, d, J=9.0 Hz), 7.67 (1H, d,J÷9.0 Hz), 8.20 (1H, m).

EXAMPLE 474 Synthesis of 4-(trifluoromethyl)-1H-indazol-5-ol

A suspension of the 5-methoxy-4-(trifluoromethyl)-1H-indazole (395 mg,1.83 mmol) obtained in Example 473 in dichloromethane (5.0 ml) wascooled to −30 to −40° C., and then a 1M boron tribromide/dichloromethanesolution (3.84 ml, 3.84 mmol) was added dropwise thereto over a periodof 5 minutes. The resulting mixture was slowly heated from −30° C. to20° C. and stirred for 5.5 hours while maintaining the temperature. Theresulting reaction solution was cooled to 0 to 5° C., poured into icewater, adjusted to pH 5 to 6 with a 5% aqueous sodium hydrogencarbonatesolution, and then extracted with chloroform (an insoluble material waspresent) and then ethyl acetate. Each organic phase was washed with a 5%aqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, and then filtered, and the filtrate was concentrated underreduced pressure. A crude product (280 mg) composed mainly of thestarting 5-methoxy-4-(trifluoromethyl)-1H-indazole was obtained from thechloroform phase, and a crude product (145 mg) composed mainly of4-(trifluoromethyl)-1H-indazol-5-ol was obtained from the ethyl acetatephase. The latter crude product was purified by a silica gel columnchromatography (eluent: chloroform/ethyl acetate=4/1) to obtain4-(trifluoromethyl)-1H-indazol-5-ol (95 mg, 26%).

¹H-NMR (DMSO-d₆) δ; 7.12 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=8.8 Hz), 7.91(1H, m), 10, 23 (1H, s), 13.25 (1H, brs).

The following compound of Example 475 was synthesized by carrying outreaction according to the method described in Example 407, except forusing the 4-(trifluoromethyl)-1H-indazol-5-ol obtained in Example 474,as a starting material.

EXAMPLE 475 5-(Azepan-4-yloxy)-4-(trifluoromethyl)-1H-indazole

¹H-NMR (CDCl₃) δ; 1.57–1.70 (1H, m), 1.85–2.20 (5H, m), 2.86–3.12 (4H,m), 4.72 (1H, m), 7.19 (1H, d, J=9.1 Hz), 7.61 (1H, d, J=9.1 Hz), 8.16(1H, m).

EXAMPLE 476 Synthesis of 2-(1H-indazol-5-yloxy)aniline

Under a hydrogen atmosphere at atmospheric pressure, a solution of the5-(2-nitrophenoxy)-1H-indazole (56.7 mg, 0.222 mmol) obtained in Example352 in a mixture of ethyl acetate (3 ml) and methanol (3 ml) was stirredat room temperature for 1.5 hours. The solution was filtered and thenthe filtrate was concentrated to obtain 2-(1H-indazol-5-yloxy)aniline(34.5 mg, 69%).

MS: m/z=226 (M+1)

EXAMPLE 477 Synthesis of N-[2-(1H-indazol-5-yloxy)phenyl]acetamide

Acetic anhydride (0.04 ml) was added to a solution of the2-(1H-indazol-5-yloxy)aniline (34 mg, 0.151 mmol) obtained in Example476 in pyridine (1 ml) at room temperature, and the resulting mixturewas stirred at room temperature for 2 hours. The reaction solution wascooled to 0° C. and a saturated aqueous sodium hydrogencarbonatesolution was added thereto, followed by extraction with ethyl acetate.The organic layer was washed with a saturated aqueous sodium chloridesolution and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure and the resulting residue wasdissolved in a mixed solution of tetrahydrofuran (1 ml) and methanol (1ml), followed by adding thereto 1N aqueous sodium hydroxide solution (1ml). The resulting mixture was stirred at room temperature for 1 hour.The reaction solution was added to a saturated aqueous sodium chloridesolution and extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent, and the resulting residue was purified by a silica gelcolumn chromatography (chloroform/methanol) to obtainN-[2-(1H-indazol-5-yloxy)phenyl]acetamide (32 mg, 79%).

¹H-NMR (DMSO-d₆) δ; 2.05 (3H, s), 6.70–6.79 (1H, m), 6.95–7.10 (3H, m),7.12 (1H, dd, J=2.0, 9.0 Hz), 7.32 (1H, d, J=2.0 Hz), 7.57 (1H, d, J=9.0Hz), 7.95–8.05 (2H, m), 9.49 (1H, s), 13.09 (1H, brs)

EXAMPLE 478 Synthesis of methyl 2-(1H-indazol-5-yloxy)benzoate (a)Synthesis of methyl 2-(3-methyl-4-nitrophenoxy)benzoate

Potassium carbonate (1.16 g, 8.39 mmol) was added to a solution of5-fluoro-2-nitrotoluene (1.0 g, 6.45 mmol) and methyl salicylate (1.18g, 7.74 mmol) in N,N-dimethylformamide (8 ml), and the resulting mixturewas stirred at 140° C. for 1 hour. After the reaction, the reactionsolution was cooled to 0° C. and a saturated aqueous sodium chloridesolution was added thereto, followed by extraction with ethyl acetate.The organic layer was washed with water and a saturated aqueous sodiumchloride solution, and dried over anhydrous sodium sulfate. The organiclayer dried was concentrated and then purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate=10/1) to obtain methyl2-(3-methyl-4-nitrophenoxy)benzoate (1.88 g, 85%).

¹H-NMR (CDCl₃) δ; 2.59 (3H, s), 3.78 (3H, s), 6.70–6.82 (2H, m), 7.12(1H, dd, J=11, 8.0 Hz), 7.35 (1H, ddd, J=1.1, 7.5, 7.5 Hz), 7.56–7.65(1H, m), 8.02 (1H, dd, J=1.3, 7.5 Hz), 8.05 (1H, d, J=8.0 Hz).

(b) Synthesis of methyl 2-(4-amino-3-methylphenoxy)-benzoate

Under a hydrogen atmosphere at atmospheric pressure, a solution ofmethyl 2-(3-methyl-4-nitrophenoxy)-benzoate (1.85 g, 6.44 mmol) in amixture of ethyl acetate (15 ml) and methanol (8 ml) was stirred at roomtemperature for 5 hours. The solution was filtered and the filtrate wasconcentrated to obtain methyl 2-(4-amino-3-methylphenoxy)-benzoate (1.52g, 92%).

¹H-NMR (CDCl₃) δ; 2.16 (3H, s), 3.87 (3H, s), 6.65–6.82 (3H, m), 6.85(1H, dd, J=1.1, 8.4 Hz), 7.06 (1H, dd, J=1.1, 7.7 Hz), 7.30–7.40 (1H,m), 7.85 (1H, dd, J=1.7, 7.7 Hz).

(c) Synthesis of methyl 2-(1H-indazol-5-yloxy)benzoate

Methyl 2-(4-amino-3-methylphenoxy)benzoate (500 mg, 1.94 mmol) wassuspended in water (5.7 ml), followed by adding thereto concentratedhydrochloric acid (1.0 ml) and ammonium tetrafluoroborate (693 mg) at 0°C. An aqueous sodium nitrite solution (134 mg/1 ml) was added dropwiseto the suspension. A saturated aqueous sodium chloride solution wasadded thereto, followed by extraction with chloroform. The organic layerwas dried over anhydrous sodium sulfate and concentrated. The resultingdark-blue oil was dissolved in chloroform (15 ml), and potassium acetate(381 mg, 3.88 mmol) and 18-crown-6 (15 mg) were added thereto at roomtemperature and then stirred for 2 hours. To the resulting suspensionwas added a saturated aqueous sodium chloride solution, followed byextraction with chloroform. The organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The organic layer dried was concentrated and thenpurified by a silica gel column chromatography(chloroform/methanol=70/1) to obtain methyl2-(1H-indazol-5-yloxy)benzoate (157 mg, two steps 30%).

¹H-NMR (CDCl₃) δ; 3.85 (3H, s), 6.92 (1H, dd, J=1.0, 8.3 Hz), 7.12–7.28(3H, m), 7.40–7.52 (2H, m), 7.92 (1H, dd, J=1.8, 7.9 Hz), 8.00 (1H, s).

EXAMPLE 479 Synthesis of 2-(1H-indazol-5-yloxy)benzoic Acid

The methyl 2-(1H-indazol-5-yloxy)benzoate (960 mg, 3.58 mmol)synthesized in Example 478 was dissolved in a mixture of tetrahydrofuran(10 ml) and methanol (5 ml), and a 1N-aqueous sodium hydroxide solution(7 ml) was added thereto at room temperature and then stirred at 60° C.for 40 minutes. After the reaction, the reaction solution was cooled to0° C., adjusted to pH 4 with a 2N-aqueous hydrochloric acid solution,and then extracted with ethyl acetate. The organic layer was washed witha saturated aqueous sodium chloride solution, dried over anhydroussodium sulfate, and then concentrated to obtain2-(1H-indazol-5-yloxy)benzoic acid (790 mg, 86%).

MS: m/z=255 (M+1)

EXAMPLE 480 Synthesis of 2-(1H-indazol-5-yloxy)-N-isobutylbenzamide

The 2-(1H-indazol-5-yloxy)benzoic acid (80.6 mg, 0.317 mmol) synthesizedin Example 479 and isobutylamine (301 mg, 0.412 mmol) were dissolved inN,N-dimethylformamide (2 ml), and dimethylamine hydrochloride (72.5 mg,0.380 mmol), hydroxybenzotriazole (47.1 mg, 0.349 mmol) andtriethylamine (0.09 ml, 0.634 mmol) were added thereto at roomtemperature and then stirred for 2.5 hours. After the reaction, asaturated aqueous sodium hydrogencarbonate solution was added thereto,followed by extraction with chloroform. The organic layer was washedwith a saturated aqueous sodium chloride solution, dried over anhydroussodium sulfate, and then concentrated to obtain2-(1H-indazol-5-yloxy)-N-isobutylbenzamide (47 mg, 48%) as a brownsolid.

¹H-NMR (DMSO-d₆) δ; 0.80 (6H, d, J=6.8 Hz), 1.60–1.80 (1H, m), 3.06 (2H,t, J=6.3 Hz), 6.79 (1H, d, J=8.3 Hz), 7.10–7.30 (2H, m), 7.30–7.45 (2H,m), 7.50–7.70 (2H, m), 8.02 (1H, s), 8.22 (1H, brs), 13.1 (1H, brs).

EXAMPLE 481 Synthesis of 2-(1H-indazol-5-yloxy)-N,N-dimethylbenzamide

The 2-(1H-indazol-5-yloxy)benzoic acid (80.8 mg, 0.318 mmol) synthesizedin Example 479 and dimethylamine hydrochloride (33.7 mg, 0.413 mmol)were dissolved in N,N-dimethylformamide (2 ml), and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (72.5mg, 0.380 mmol), hydroxybenzotriazole (47.1 mg, 0.349 mmol) andtriethylamine (0.13 ml, 0.954 mmol) were added thereto at roomtemperature and then stirred for 2.5 hours. After the reaction, asaturated aqueous sodium hydrogencarbonate solution was added thereto,followed by extraction with chloroform. The organic layer was washedwith a saturated aqueous sodium chloride solution, dried over anhydroussodium sulfate, and then concentrated to obtain2-(1H-indazol-5-yloxy)-N,N-dimethylbenzamide (51 mg, 57%).

¹H-NMR (DMSO-d₆) δ; 2.93 (3H, s), 2.89 (3H, s), 6.78 (1H, d, J=9.2 Hz),7.05–7.20 (2H, m), 7.40–7.62 (3H, m), 7.57 (1H, d, J=9.2 Hz), 8.02 (1H,s), 13.1 (1H, brs)

EXAMPLE 482 Synthesis of 3-(1H-indazol-5-yloxy)-N,N-dimethylbenzamide(a) Synthesis of 3-(1H-indazol-5-yloxy)benzoic acid

3-(1H-indazol-5-yloxy)benzoic acid was synthesized by carrying outreaction according to the method described in Example 479, except forusing methyl 3-hydroxybenzoate as a starting material.

(b) Synthesis of 3-(1H-indazol-5-yloxy)-N,N-dimethylbenzamide

3-(1H-indazol-5-yloxy)-N,N-dimethylbenzamide was synthesized by carryingout reaction according to the method described in Example 481, exceptfor using 3-(1H-indazol-5-yloxy)benzoic acid as a starting material.

MS: m/z=282 (M+1)

EXAMPLE 483 Synthesis of [2-(1H-indazol-5-yloxy)phenyl]-methanol

The methyl 2-(1H-indazol-5-yloxy)benzoate (95.6 g, 0.36 mmol) obtainedin Example 478 was dissolved in tetrahydrofuran (5 ml), and lithiumaluminum hydride (44.1 mg, 1.07 mmol) was added thereto at 0° C. andstirred for 30 minutes. Water (0.3 ml), a 2N-aqueous sodium hydroxidesolution (0.6 ml) and water (0.9 ml) was added dropwise thereto in thatorder, and the precipitate formed was removed by filtration. A saturatedaqueous sodium hydrogencarbonate solution was added to the filtrate,followed by extraction with ethyl acetate. The organic layer was washedwith a saturated aqueous sodium chloride solution, dried over anhydroussodium sulfate, and then concentrated to obtain[2-(1H-indazol-5-yloxy)phenyl]methanol (56 mg, 65%).

MS: m/z=241 (M+1)

EXAMPLE 484 Synthesis of1-[2-(1H-indazol-5-yloxy)phenyl]-N,N-dimethylmethanaminemonohydrochloride (a) Synthesis of1-[2-(1H-indazol-5-yloxy)phenyl]-N,N-dimethylmethanamine

1-[2-(1H-indazol-5-yloxy)phenyl]-N,N-dimethylmethanamine was synthesizedby carrying out reaction according to the method described in Example483, except for using the 2-(1H-indazol-5-yloxy)-N,N-dimethylbenzamideobtained in Example 481, as a starting material.

MS: m/z=268 (M+1)

(b) Synthesis of1-[2-(1H-indazol-5-yloxy)phenyl]-N,N-dimethylmethanamineMonohydrochloride

1-[2-(1H-indazol-5-yloxy)phenyl]-N,N-dimethylmethanamine was dissolvedin diethyl ether (2 ml), and a 1N-hydrochloric acid/diethyl ethersolution (0.3 ml) was added dropwise thereto at 0° C. The resultingsuspension was concentrated to obtain1-[2-(1H-indazol-5-yloxy)phenyl]-N,N-dimethylmethanaminemonohydrochloride (20 mg).

MS: m/z=268 (M+1)

EXAMPLE 485 Synthesis ofN-[2-(1H-indazol-5-yloxy)benzyl]-2-methylpropan-1-aminemonohydrochloride

N-[2-(1H-indazol-5-yloxy)benzyl]-2-methylpropan-1-aminemonohydrochloride was synthesized by carrying out reaction according tothe method described in Example 484, except for using the2-(1H-indazol-5-yloxy)-N-isobutylbenzamide obtained in Example 480, as astarting material.

MS: m/z=296 (M+1)

The following compound of Example 486 was synthesized by carrying outreaction according to the method described in Example 403, (a), exceptfor using the 5-(4-piperidinyloxy)-1H-indazole obtained in Example 42,as a starting material.

EXAMPLE 486 5-[(1-Acetylpiperidin-4-yl)oxy]-1H-indazole

MS: m/z=260 (M+1)

The following compound of Example 487 was synthesized by carrying outreaction according to the method described in Example 140, except forusing the 5-(4-piperidinyloxy)-1H-indazole obtained in Example 42, as astarting material.

EXAMPLE 487 Synthesis of 5-[(1-methylpiperidin-4-yl)oxy]-1H-indazole

MS: m/z=232 (M+1)

The following compound of Example 488 was synthesized by carrying outreaction according to the method described in Example 399, except forusing the 5-[(1-acetylpiperidin-4-yl)oxy]-1H-indazole obtained inExample 486, as a starting material.

EXAMPLE 488 Synthesis of 5-[(1-ethylpiperidin-4-yl)oxy]-1H-indazole

MS: m/z=246 (M+1)

EXAMPLE 489 Synthesis of5-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-1H-indazole

To a solution of the 5-(4-piperidinyloxy)-1H-indazole (100 mg, 0.460mmol) obtained in Example 42 in N,N-dimethylformamide (3 ml) were added(2-bromoethyl)methyl ether (76.8 mg, 0.552 mmol) and potassium carbonate(159 mg, 1.15 mmol), and the resulting mixture was stirred overnight atroom temperature. Then, the reaction solution was cooled to 0° C. and asaturated aqueous sodium hydrogencarbonate solution was added thereto,followed by extraction with ethyl acetate. The organic layer was washedwith a saturated aqueous sodium chloride solution and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure and the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol) to obtain5-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-1H-indazole (52 mg, 41%).

MS: m/z=276 (M+1)

The following compounds of Example 490 and Example 491 were synthesizedby carrying out reaction according to the method described in Example489.

EXAMPLE 490

5-{[1-(Cyclohexylmethyl)piperidin-4-yl]oxy}-1H-indazole

MS: m/z=314 (M+1)

EXAMPLE 491

5-{[1-(Cyclobutylmethyl)piperidin-4-yl]oxy}-1H-indazole

MS: m/z=286 (M+1)

The following compounds of Example 492 and Example 493 were synthesizedby carrying out reaction according to the method described in Example489, except for using the 1H-indazol-5-ol obtained in Reference Example4, as a starting material.

EXAMPLE 492 2-(1H-indazol-5-yloxy)nicotinonitrile

MS: m/z=237 (M+1)

EXAMPLE 493 2-(1H-indazol-5-yloxy)benzonitrile

MS: m/z=236 (M+1)

EXAMPLE 494 Synthesis of 5-(8-azabicyclo[3.2.1]oct-3-yloxy)-1H-indazole(a) Synthesis of 8-benzyl-8-azabicyclo[3.2.1]octan-3-ol

In tetrahydrofuran (16 ml) was dissolved8-benzyl-8-azabicyclo[3.2.1]octan-3-one (1.0 g, 4.64 mmol), and a1M-diisobutylaluminum hydride/toluene solution (11.6 ml, 11.6 mmol) wasadded dropwise thereto at −78° C. over a period of 10 minutes andstirred for another 1 hour. Water was added dropwise thereto to quenchthe excess reactants, and the resulting mixture was separated by theaddition of a 2N-aqueous hydrochloric acid solution and ethyl acetate.The aqueous layer was adjusted to pH 10 or lower with a 2N-aqueoussodium hydroxide solution and then extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous sodium sulfate, and then concentrated toobtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-ol (886 mg, 88%).

¹H-NMR (CDCl₃) δ; 1.50–1.75 (4H, m), 1.78–1.85 (m), 1.95–2.20 (6H, m),3.14 (2H, br), 3.23 (br), 3.52 (2H, s), 3.61 (2H, s), 3.94 (1H, m), 7.40(1H, t, J=4.3 Hz), 7.18–7.40 (5H, m).

(b) tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate

In ethanol (20 ml) was dissolved 8-benzyl-8-azabicyclo[3.2.1]octan-3-ol(740 mg, 3.41 mmol), followed by adding thereto ammonium formate (740mg) and 10%-palladium/carbon (148 mg) at room temperature, and theresulting mixture was refluxed for 2 hours. After the mixture wasfiltered, the filtrate was concentrated and the resulting residue wasdissolved in diethyl ether. A 1N-hydrochloric acid/diethyl ethersolution was added dropwise thereto in excess and the resulting mixturewas concentrated. The residue was dissolved in methanol (20 ml), anddi-tert-butyl dicarbonate (890 mg, 4.09 mmol) and triethylamine (1.0 ml,6.82 mmol) were added thereto at 0° C. and stirred at room temperaturefor 2 hours. After the reaction, a saturated aqueous sodiumhydrogencarbonate solution was added to the reaction solution, followedby extraction with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and then concentrated to obtain tert-butyl3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (717 mg, two steps93%).

¹H-NMR (CDCl₃) δ; 1.46 (9H, s), 1.47 (s), 1.42–1.74 (4H, m), 1.94 (2H,br), 2.14 (2H, br), 4.14 (2H, br), 4.21 (1H, br).

(c) Synthesis of 5-(8-azabicyclo[3.2.1]oct-3-yloxy)-1H-indazole

Except for using tert-butyl3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate,5-(8-azabicyclo[3.2.1]oct-3-yloxy)-1H-indazole was synthesized bycarrying out reaction according to the method described in Example 4.

MS: m/z=244 (M+1)

EXAMPLE 495 Synthesis of4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (a)Synthesis of 2,3-dimethyl-4-nitrophenyl trifluoromethanesulfonate

Anhydrous trifluoromethanesulfonate (3.17 ml, 18.8 mmol) andtriethylamine (2.75 ml, 19.7 mmol) were added dropwise to a solution of2,3-dimethyl-4-nitrophenol (3.0 g, 17.9 mmol) in methylene chloride (60ml) at 0° C. and stirred at room temperature for 1 hour. Then, thereaction solution was poured into water and extracted with chloroform.The organic layer was dried over magnesium sulfate and distilled toremove the solvent, and the resulting residue was purified by a silicagel column chromatography (eluent: hexane/ethyl acetate) to obtain2,3-dimethyl-4-nitrophenyl trifluoromethanesulfonate (5.32 g, 99%).

(b) Synthesis of 2,3-dimethyl-4-nitrobenzonitrile

Potassium cyanide (2.26 g, 34.7 mmol) was added to a solution of2,3-dimethyl-4-nitrophenyl trifluoromethane-sulfonate (5.20 g, 17.4mmol) in tetrahydrofuran (21 ml) at room temperature, followed bydeaeration. After tetrakistriphenylphosphine (1.00 g, 0.865 mmol) wasadded thereto, deaeration was conducted again and then the reaction wascarried out under reflux conditions for 10 hours. A 0.5M-aqueouspotassium hydrogensulfate solution and then water were added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was dried over magnesium sulfate and distilled to removethe solvent, and the resulting residue was purified by a silica gelcolumn chromatography (eluent: n-hexane/chloroform) to obtain2,3-dimethyl-4-nitrobenzonitrile (2.79 g, 90.9%).

¹H-NMR (DMSO-d₆) δ; 2.26 (3H, s), 2.49 (3H, s), 7.78 (1H, d, J=8.4 Hz),7.85 (1H, d, J=8.4 Hz).

(c) Synthesis of 4-amino-2,3-dimethylbenzonitrile

Tin dichloride (12.24 g, 54.2 mmol) was added to a solution of2,3-dimethyl-4-nitrobenzonitrile (2.73 g, 15.5 mmol) in ethanol (94 ml)at room temperature, and the reaction was carried out for 5 hours underreflux conditions. After cooling, the reaction mixture was concentrated,and the resulting residue was diluted with ethyl acetate and then washedwith a saturated aqueous sodium hydrogencarbonate solution. After theinsoluble material was filtered off, the filtrate was separated and theorganic layer was washed with a saturated aqueous sodium chloridesolution. The organic layer was dried over magnesium sulfate anddistilled to remove the solvent, whereby4-amino-2,3-dimethylbenzonitrile (2.12 g, 93.6%) was obtained.

¹H-NMR (DMSO-d₆) δ; 1.97 (3H, s), 2.30 (3H, s), 5.79 (2H, brs), 6.53(1H, d, J=8.4 Hz), 7.20 (1H, d, J=8.4 Hz).

(e) Synthesis of N-(4-cyano-2,3-dimethylphenyl)acetamide

Acetic anhydride (1.36 ml, 14.4 mmol) was added to a solution of4-amino-2,3-dimethylbenzonitrile (1.32 g, 9.03 mmol) in ethyl acetate(10 ml) at room temperature, and then the reaction was carried out for 4hours under reflux conditions. After the reaction mixture was cooled,the precipitate obtained was collected by filtration and dried to obtainN-(4-cyano-2,3-dimethylphenyl)acetamide (1.39 g, 81.8%).

¹H-NMR (DMSO-d₆) δ; 2.09 (3H, s), 2.14 (3H, s), 2.43 (3H, s), 7.50 (1H,d, J=9.0 Hz), 7.55 (1H, d, J=8.3 Hz), 9.56 (1H, br s).

(f) Synthesis of 4-methyl-1H-indazole-5-carbonitrile

Acetic anhydride (2.1 ml, 22.3 mmol), tetra-n-butylammonium bromide (118mg, 0.366 mmol), potassium acetate (1.44 g, 14.7 mmol) and isoamylnitrite (1.3 ml, 9.68 mmol) were added to an ethyl acetate suspension(15 ml) of N-(4-cyano-2,3-dimethylphenyl)acetamide (1.38 g, 7.33 mmol)at room temperature, and then the reaction was carried out for 7 hoursunder reflux conditions. The reaction mixture was cooled, diluted withethyl acetate, and then washed with a saturated aqueous sodiumhydrogencarbonate solution. The organic layer was washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and then distilled to remove the solvent, and the resultingresidue was purified by a silica gel column chromatography (eluent:n-hexane/chloroform) to obtain 4-methyl-1H-indazole-5-carbonitrile (1.24g, 84.9%).

¹H-NMR (DMSO-d₆) δ; 2.81 (3H, s), 2.84 (3H, s), 7.72 (1H, d, J=8.8 Hz),8.23 (1H, d, J=0.7 Hz), 8.37 (1H, d, J=8.8 Hz).

(g) Synthesis of 4-methyl-1H-indazole-5-carboxylic acid

Water (2 ml) and concentrated sulfuric acid (2 ml) were added to aacetic acid suspension (2 ml) of 4-methyl-1H-indazole-5-carbonitrile(399 mg, 2.00 mmol) at room temperature, and then the reaction wascarried out for 18 hours under reflux conditions. The reaction mixturewas poured onto ice (20 g) and the precipitate was collected byfiltration and dried to obtain 4-methyl-1H-indazole-5-carboxylic acid(247 mg, 70.1%).

¹H-NMR (DMSO-d₆) δ; 2.82 (s, 3H), 7.37 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.8Hz, 1H), 8.31 (d, J=1.1 Hz, 1H).

(h) Synthesis of4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide

Tetrahydro-2H-pyran-4-ylamine monohydrochloride (228 mg, 1.66 mmol),triethylamine (0.5 ml, 3.59 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (367mg, 1.91 mmol) and hydroxybenzotriazole (190 mg, 1.41 mmol) were addedto a solution of 4-methyl-1H-indazole-5-carboxylic acid (225 mg, 1.28mmol) in N,N-dimethylformamide (5.5 ml), and the resulting mixture wasstirred at room temperature for 4 hours. After completion of thereaction, the reaction mixture was diluted with ethyl acetate and washedwith a saturated aqueous sodium hydrogencarbonate solution. A smallamount of the insoluble material was collected by filtration and thendried to obtain4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (41 mg).The filtrate was extracted with ethyl acetate and chloroform, and thecombined organic layer was dehydrated over magnesium sulfate and thenfiltered. The filtrate was concentrated and the resulting residue wassuspended in chloroform. The resulting suspension was filtered and theprecipitate was dried to obtain4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (134 mg,52.7%).

¹H-NMR (DMSO-d₆) δ; 1.45–1.58 (m, 2H), 1.76–1.80 (m, 2H), 2.58 (s, 3H),3.33–3.42 (m, 2H), 3.84–4.03 (m, 3H), 7.29 (d, J=8.6 Hz, 1H), 7.35 (d,J=8.6 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 8.19 (d, J=0.9 Hz, 1H), 13.11(br, 1H).

The following compound of Example 496 was synthesized by carrying outreaction according to the method described in Example 495.

EXAMPLE 496 tert-Butyl3-{[(4-methyl-1H-indazol-5-yl)carbonyl]amino}cyclohexylcarbamate

MS: m/z=373 (M+1)

The following compound of Example 497 was synthesized by carrying outreaction according to the method described in Example 42, (b), exceptfor using the tert-butyl3-{[(4-methyl-1H-indazol-5-yl)carbonyl]amino}cyclohexylcarbamateobtained in Example 496, as a starting material.

EXAMPLE 497 N-(3-aminocyclohexyl)-4-methyl-1H-indazole-5-carboxamide

MS: m/z=273 (M+1)

EXAMPLE 498 Synthesis of6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (a)Synthesis of dimethyl 2,5-dimethylterephthalate

A suspension of 2,5-dimethylterephthalic acid (3.67 g, 18.9 mmol) inmethanol (70 ml) was cooled with ice water, followed by adding dropwisethereto thionyl chloride (7.0 ml, 96 mmol), and the resulting mixturewas stirred for 3 hours with heating under reflux. The resultingsolution was cooled to room temperature to precipitate a solid. Thesolid was collected by filtration and the precipitate on a filter waswashed with methanol (once) and hexane (twice) and dried under reducedpressure to obtain dimethyl 2,5-dimethylterephthalate (3.29 g, 78%). Thesolvent was distilled off from the filtrate under reduced pressure, anda saturated aqueous sodium hydrogencarbonate solution was added to theresidue, followed by extraction with ethyl acetate (twice). The extractsolution was dried over anhydrous magnesium sulfate. The solvent wasdistilled off to obtain dimethyl 2,5-dimethylterephthalate (0.916 g,22%, total: >99%) additionally.

(b) Synthesis of 4-(methoxycarbonyl)-2,5-dimethylbenzoic acid

Methanol (20 ml) was added to a solution of dimethyl2,5-dimethylterephthalate (3.95 g, 17.8 mmol) in tetrahydrofuran (40 ml)and the resulting mixture was cooled on a water bath. A 2N-aqueouslithium hydroxide solution (9.8 ml, 19.6 mmol) was slowly added theretoand stirred for 3 hours. The solvent was distilled off under reducedpressure and the residue was adjusted to pH 1 to 2 with a1N-hydrochloric acid and extracted with ethyl acetate (×3). The extractsolution was dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure and the residue was purified by asilica gel chromatography (eluent: chloroform/methanol=30/1) to obtain4-(methoxycarbonyl)-2,5-dimethylbenzoic acid (2.77 g, 75%).

(c) Synthesis of methyl4-[(tert-butoxycarbonyl)amino]-2,5-dimethybenzoate

The title compound was synthesized by carrying out reaction according tothe method described in Example 4, (a), except for using4-(methoxycarbonyl)-2,5-dimethylbenzoic acid as a starting material.

(d) Synthesis of methyl 4-amino-2,5-dimethylbenzoate monohydrochloride

The title compound was synthesized by carrying out reaction according tothe method described in Example 4, (b), except for using4-(methoxycarbonyl)-2,5-dimethylbenzoic acid as a starting material.

(e) Synthesis of methyl 4-(acetylamino)-2,5-dimethylbenzoate

Triethylamine (1.16 ml, 8.32 mmol) was added to a suspension of methyl4-amino-2,5-dimethylbenzoate monohydrochloride (0.600 g, 2.78 mmol) indichloromethane (8 ml), and the resulting mixture was cooled with icewater, followed by adding dropwise thereto a solution of acetyl chloride(0.263 g, 3.35 mmol) in dichloromethane (2 ml). The resulting mixturewas heated to room temperature and stirred for 3 hours, and then acetylchloride (0.262 g, 3.34 mmol) was further added thereto and stirred for1.5 hours. The resulting mixture was added to a saturated aqueous sodiumhydrogencarbonate solution and extracted three times with ethyl acetate,and the organic layer was washed with a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate. Thesolvent was distilled off to obtain methyl4-(acetylamino)-2,5-dimethylbenzoate (0.685 g, 99%).

(f) Synthesis of methyl 1-acetyl-6-methyl-1H-indazole-5-carboxylate

Acetic anhydride (0.85 ml, 9.01 mmol), n-butylammonium bromide (0.0502g, 0.156 mmol) and potassium acetate (0.587 g, 5.98 mmol) were added toa solution of methyl 4-(acetylamino)-2,5-dimethylbenzoate (0.661 g, 2.99mmol) in ethyl acetate (5 ml), followed by adding thereto a solution ofisoamyl nitrite (0.0458 g, 3.91 mmol) in ethyl acetate (2 ml), and theresulting mixture was stirred for 8 hours with heating under reflux.Water was added thereto, followed by extraction with ethyl acetate(three times), and the extract solution was dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (hexane/ethyl acetate=5/1 to 1/1). The solid thusobtained was suspended in hexane and stirred to be washed, and then itwas collected by filtration and dried under reduced pressure to obtainmethyl 1-acetyl-6-methyl-1H-indazole-5-carboxylate (0.0731 g, 11%).

(g) Synthesis of 6-methyl-1H-indazole-5-carboxylic acid

A 2N-aqueous sodium hydroxide solution (0.63 ml, 1.3 mmol) was added toa solution of methyl 1-acetyl-6-methyl-1H-indazole-5-carboxylate (0.0731g, 0.315 mmol) in tetrahydrofuran (1 ml), and the resulting mixture wasstirred for 3 hours with heating under reflux. Then, a 2N-aqueouslithium hydroxide solution (0.63 ml, 1.3 mmol) was added thereto andstirred for another 3 hours. The resulting solution was diluted withwater and washed with diethyl ether, and the aqueous layer was adjustedto pH 1 to 2 with 1N-hydrochloric acid to precipitate a solid. The solidprecipitated was collected by filtration and the precipitate on a filterwas washed with water and dried under reduced pressure to obtain6-methyl-1H-indazole-5-carboxylic acid (0.0514 g, 93%).

(h) Synthesis of6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide

Tetrahydro-2H-pyran-4-ylamine monohydrochloride (0.0402 g, 0.292 mmol),triethylamine (0.07 ml, 0.5 mmol), 1-hydroxybenztriazole (0.0460 g,0.340 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidemonohydrochloride (0.0606 g, 0.316 mmol) were added to a solution of6-methyl-1H-indazole-5-carboxylic acid (0.0437 g, 0.248 mmol) inN,N-dimethylformamide (2 ml) and stirred overnight. A saturated aqueoussodium hydrogencarbonate solution was added thereto, followed byextraction with chloroform (×3), and the extract solution was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, followed by replacement with toluene (three times), whereby asolid was precipitated. The solid obtained was suspended in ethylacetate and stirred to be washed, and then it was collected byfiltration and dried under reduced pressure to obtain6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (0.0587 g,91%).

¹H-NMR (DMSO-d₆) δ; 1.46–1.58 (2H, m), 1.75–1.82 (2H, m), 2.44 (3H, s),3.39 (2H, td, J=1.9, 11.6 Hz), 3.83–3.90 (2H, m), 3.91–4.02 (1H, m),7.35 (1H, m), 7.73 (1H, s), 8.06 (1H, s), 8.23 (1H, d, J=7.7 Hz), 13.01(1H, br).

EXAMPLE 499 Synthesis ofN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine(a) Synthesis ofethyl(5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazol-4-yl)acetate

A solution of potassium tert-butoxide (2.02 g, 18.0 mmol) intetrahydrofuran (20 ml) was added dropwise to a solution of the5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (1.85 g, 7.48 mmol)obtained in Example 317, (d) and ethyl chloroacetate (960 μl, 9.01 mmol)in tetrahydrofuran (10 ml) at −40° C. over a period of 15 minutes, andstirred at −40° C. for 1 hour. The reaction was terminated by pouring1N-hydrochloric acid, and the reaction solution was extracted with ethylacetate. The extract solution was washed with a saturated aqueous sodiumchloride solution, dried over sodium sulfate, and then distilled underreduced pressure to remove the solvent, whereby a crude product wasobtained. The crude product was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate=4/1) to obtainethyl(5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazol-4-yl)acetate (1.93g, 78%).

¹H-NMR (DMSO-d₆) δ; 1.26 (3H, t, J=7.1 Hz), 1.74 (3H, m), 2.13 (2H, m),2.51 (1H, m), 3.77 (1H, m), 4.01 (1H, m), 4.19 (2H, q, J=7.1 Hz), 4.35(2H, s), 5.76 (1H, dd, J=2.6, 8.8 Hz), 7.63 (1H, d, J=9.2 Hz), 8.21 (1H,d, J=8.0 Hz), 8.22 (1H, s).

(b) Synthesis of 4-methyl-5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole

A 1N-aqueous sodium hydroxide solution (8.64 ml, 8.64 mmol) was added toa solution of ethyl(5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazol-4-yl)acetate (1.92 g,5.76 mmol) in dioxane (20 ml), and the resulting mixture was stirred atroom temperature for 3 hours. The solvent was distilled off underreduced pressure, and water, ethyl acetate and 1N-hydrochloric acid wereadded to the residue. The resulting mixture was extracted with ethylacetate, and the extract solution was washed with a saturated aqueoussodium chloride solution, dried over sodium sulfate, and then distilledunder reduced pressure to remove the solvent, whereby(5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazol-4-yl)acetic acid wasobtained. N,N-dimethyl-formamide (20 ml) and then potassium carbonate(800 mg, 5.79 mmol) were added thereto, and the resulting mixture wasstirred at 50° C. for 30 minutes. Water, ethyl acetate, toluene and1N-hydrochloric acid were added thereto, followed by extraction withethyl acetate/toluene=1/1, and the extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent, whereby4-methyl-5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (1.39 g, 93%)was obtained.

¹H-NMR (CDCl₃) δ; 1.74 (3H, m), 2.13 (2H, m), 2.51 (1H, m), 2.90 (3H,s), 3.78 (1H, m), 4.02 (1H, m), 5.74 (1H, dd, J=2.7, 9.1 Hz), 7.50 (1H,d, J=9.2 Hz), 8.10 (1H, d, J=9.2 Hz), 8.23 (1H, s).

(c) Synthesis of 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine

To a solution of 4-methyl-5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole(1.06 g, 4.06 mmol) in ethanol (20 ml) were added 10% Pd—C (200 mg) andammonium formate (1.28 g, 20.3 mmol), and the resulting mixture washeated under reflux for 1 hour. After the solid was removed byfiltration using Celite, water, ethyl acetate and a saturated aqueoussodium hydrogencarbonate solution were added to the residue. Theresulting mixture was extracted with ethyl acetate, and the extractsolution was washed with a saturated aqueous sodium chloride solution,dried over sodium sulfate, and then distilled under reduced pressure toremove the solvent, whereby4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (955 mg, 100%)was obtained.

¹H-NMR (CDCl₃) δ; 1.74 (3H, m), 2.11 (2H, m), 2.36 (3H, s), 2.53 (1H,m), 3.51 (2H, br), 3.72 (1H, m), 4.01 (1H, m), 5.63 (1H, dd, J=2.7, 9.4Hz), 6.86 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=7.5 Hz), 7.90 (1H, s).

(d) Synthesis ofN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine

Sodium triacetoxyborohydride (477 mg, 2.25 mmol) and then acetic acid(99 μl, 1.73 mmol) were added to a suspension of4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (400 mg, 1.73mmol) and 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (410 mg, 1.90 mmol) in1,2-dichloroethane (5 ml), and the resulting mixture was stirred at roomtemperature for 1 day. The reaction mixture was poured into a saturatedaqueous sodium hydrogencarbonate solution and then extracted with ethylacetate. The extract solution was washed with a saturated aqueous sodiumchloride solution, dried over sodium sulfate, and then distilled underreduced pressure to remove the solvent. The residue was purified by asilica gel column chromatography (eluent: chloroform/methanol=100/2) toobtainN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine(283 mg, 38%).

¹H-NMR (CDCl₃) δ; 1.62–1.85 (7H, m), 1.99–2.23 (4H, m), 2.34 (2H, m),2.36 (3H, s), 3.23 (2H, m), 3.58 (2H, s), 3.73 (1H, m), 3.79 (1H, m),4.02 (1H, m), 5.63 (1H, dd, J=2.6, 9.6 Hz), 6.83 (1H, d, J=9.0 Hz),7.25–7.45 (6H, m), 7.91 (1H, s).

EXAMPLE 500 Synthesis ofN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine

Trifluoroacetic acid (1 ml) was added to a solution of theN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine(273 mg, 0.634 mmol) obtained in Example 499 in dichloromethane (9 ml),and the resulting mixture was stirred at room temperature for 30minutes. Then, trifluoroacetic acid (1 ml) was added thereto and stirredfor another 30 minutes, and the resulting mixture was poured into asaturated aqueous sodium hydrogencarbonate solution and extracted withchloroform. The extract solution was washed with a saturated aqueoussodium chloride solution, dried over sodium sulfate, and then distilledunder reduced pressure to remove the solvent. The residue was purifiedby a preparative thin-layer chromatography (200×200×0.5 mm, 6 plates,eluent: chloroform/methanol=6/1) to obtainN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine(142 mg, 65%).

¹H-NMR (DMSO-d₆) δ; 1.72 (2H, m), 1.99–2.23 (6H, m), 2.33 (3H, s), 3.08(2H, m), 3.51 (2H, m), 3.69 (1H, s), 4.06 (1H, m), 6.76 (1H, d, J=9.2Hz), 7.17–7.40 (6H, m), 7.90 (1H, s), 12.57 (1H, s).

EXAMPLE 501 Synthesis ofN-(8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine

To a solution of theN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine(130 mg, 0.375 mmol) obtained in Example 500 in ethanol (10 ml) wereadded 10% Pd-C (26 mg) and then ammonium formate (118 mg, 1.87 mmol),and the resulting mixture was heated under reflux for 1 hour. The solidwas removed by filtration using Celite, and the solvent was distilledoff under reduced pressure. Ethyl acetate/aqueous ammonia was added tothe residue, followed by extraction with ethyl acetate, and the extractsolution was washed with a saturated aqueous sodium chloride solution,dried over sodium sulfate, and then distilled under reduced pressure toremove the solvent, wherebyN-(8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (84 mg, 88%)was obtained.

MS: m/z=25 (M+1)

EXAMPLE 502 Synthesis ofN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine

Potassium carbonate (122 mg, 0.883 mmol) and then n-propyl bromide (40μl, 0.440 mmol) were added to a solution of theN-(8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (74 mg,0.289 mmol) obtained in Example 501 in N,N-dimethylformamide (2 ml), andthe resulting mixture was stirred at room temperature for 15 hours.After the solid was removed by filtration, the solvent was distilled offunder reduced pressure as an azeotrope with toluene. The residue waspurified by a silica gel column chromatography(chloroform/methanol/triethylamine=100/1/5) and then a preparativethin-layer chromatography (200×200×0.5 mm, 2 plates, eluent:chloroform/methanol/triethylamine=100/5/5) to obtainN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (36mg, 42%).

MS: m/z=299 (M+1)

EXAMPLE 503 Synthesis of1-(methylsulfonyl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine(a) Synthesis of 1-(methylsulfonyl)-5-nitro-1H-indazole

Methanesulfonyl chloride (887 μl, 7.20 mmol) was added to a suspensionof 5-nitroindazole (979 mg, 6.00 mmol) and triethylamine (2.0 ml, 14.3mmol) in dichloromethane (20 ml) at 0° C., and the resulting mixture wasstirred at room temperature for 3 hours. Methanesulfonyl chloride (222μl, 1.80 mmol) was further added thereto, followed by stirring foranother 1 hour. The reaction mixture was poured into a saturated aqueoussodium hydrogencarbonate solution to terminate the reaction, followed byextraction with chloroform. The extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent. Theresidue was purified by washing with methanol to obtain1-(methylsulfonyl)-5-nitro-1H-indazole (1.16 g, 80%).

¹H-NMR (CDCl₃) δ; 3.41 (3H, s), 8.23 (1H, d, J=9.4 Hz), 8.45 (1H, dd,J=2.2, 9.4 Hz), 8.47 (1H, s), 8.75 (1H, d, J=2.2 Hz).

(b) Synthesis of 1-(methylsulfonyl)-1H-indazol-5-amine

To a solution of 1-(methylsulfonyl)-5-nitro-1H-indazole (1.00 g, 4.15mmol) in ethanol (20 ml) were added 10% Pd-C (100 mg) and then ammoniumformate (1.57 g, 24.9 mmol), and the resulting mixture was heated underreflux for 1 hour. The solid was removed by filtration using Celite, andthe solvent was distilled off under reduced pressure. Ethylacetate/water was added to the residue, followed by extraction withethyl acetate, and the extract solution was washed with a saturatedaqueous sodium chloride solution, dried over sodium sulfate, and thendistilled under reduced pressure to remove the solvent, whereby1-(methylsulfonyl)-1H-indazol-5-amine (425 mg, 49%) was obtained.

¹H-NMR (CDCl₃) δ; 3.27 (3H, s), 5.26 (2H, br), 6.86 (1H, d, J=2.0 Hz),6.94 (1H, dd, J=2.0, 9.0 Hz), 7.61 (1H, d, J=9.0 Hz), 8.32 (1H, s).

(c) Synthesis of1-(methylsulfonyl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

Sodium cyanoborohydride (242 mg, 3.85 mmol) and then acetic acid (220μl, 3.84 mmol) were added to a solution of1-(methylsulfonyl)-1H-indazol-5-amine (163 mg, 0.772 mmol) and8-propyl-8-azabicyclo[3.2.1]octan-3-one (150 mg, 0.924 mmol) in methanol(3 ml), and the resulting mixture was stirred at room temperature for 4days. A 1N-aqueous sodium hydroxide solution was added thereto, followedby extraction with ethyl acetate. The extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent. Theresidue was purified successively by a silica gel column chromatography(chloroform/methanol=4/1), a preparative thin-layer chromatography(200×200×0.5 mm, 2 plates, eluent: chloroform/methanol=4/1) andpartition by LC/MS (water containing 0.05% trifluoroaceticacid-acetonitrile containing 0.035% trifluoroacetic acid, 10%–100%gradient, the extraction of the organic layer with aqueous ammonia/ethylacetate after the partition) to obtain1-(methylsulfonyl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine(8 mg, 3%).

MS: m/z=363 (M+1)

EXAMPLE 504 Synthesis of3-bromo-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (a)Synthesis of 3-bromo-5-nitro-1H-indazole

A solution of bromine (0.75 ml, 14.6 mmol) in a 2N-aqueous sodiumhydroxide solution (20 ml) was added dropwise to a mixed solution of5-nitro-1H-indazole (3.26 g, 20.0 mmol), dioxane (60 ml) and a2N-aqueous sodium hydroxide solution (30 ml) at 0° C. and stirred at 0°C. for 30 minutes and then at room temperature for 3.5 hours. An aqueoussodium hydrogensulfite solution was added thereto until a solid wasprecipitated, to terminate the reaction, followed by extraction withethyl acetate. The extract solution was washed with an aqueous sodiumthiosulfate solution and a saturated aqueous sodium chloride solution,dried over sodium sulfate, and then distilled under reduced pressure toremove the solvent. The residue was suspended in ethyl acetate andextracted with a 0.1N-aqueous sodium hydroxide solution. After 6 timesof the extraction, the combined aqueous layer was acidified withhydrochloric acid and then re-extracted with ethyl acetate. The extractsolution was washed with a saturated aqueous sodium chloride solution,dried over sodium sulfate, and then distilled under reduced pressure toremove the solvent, whereby 3-bromo-5-nitro-1H-indazole (0.93 g, 19%)was obtained.

¹H-NMR (DMSO-d₆) δ; 7.79 (1H, d, J=9.2 Hz), 8.26 (1H, dd, J=2.2, 9.4Hz), 8.48 (1H, d, J=2.2 Hz), 14.03 (1H, br).

(b) Synthesis of 3-bromo-1H-indazol-5-amine

Tin dichloride dihydrate (846 mg, 3.75 mmol) was added to a solution of3-bromo-5-nitro-1H-indazole (181 mg, 0.748 mmol) inN,N-dimethylformamide (3 ml), and the resulting mixture was stirred at70° C. for 1.5 hours. After an aqueous sodium hydrogensulfite solutionwas added thereto to terminate the reaction, ethyl acetate was added tothe reaction mixture and the insoluble material was removed byfiltration using Celite. The residue was extracted with ethylacetate/toluene, and the extract solution was washed with a saturatedaqueous sodium chloride solution, dried over sodium sulfate, and thendistilled under reduced pressure to remove the solvent, whereby3-bromo-1H-indazol-5-amine (110 mg, 69%) was obtained.

¹H-NMR (DMSO-d₆) δ; 5.01 (2H, br), 6.53 (1H, d, J=1.7 Hz), 6.84 (1H, dd,J=2.1, 8.9 Hz), 12.90 (1H, br).

(c) Synthesis of3-bromo-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

Sodium triacetoxyborohydride (159 mg, 0.750 mmol) and then acetic acid(29 μl, 0.507 mmol) were added to a suspension of3-bromo-1H-indazol-5-amine (106 mg, 0.500 mmol) and8-propyl-8-azabicyclo[3.2.1]octan-3-one (100 mg, 0.598 mmol) indichloroethane (3 ml), and the resulting mixture was stirred at roomtemperature for 1 day. Aqueous ammonia was added thereto, followed byextraction with ethyl acetate. The extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent. Theresidue was purified by a silica gel column chromatography(chloroform/methanol/triethylamine=100/10/5) and a preparativethin-layer chromatography (200×200×0.5 mm, eluent:chloroform/methanol/triethylamine=100/5/5) to obtain3-bromo-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (2mg, 1%).

¹H-NMR (CD₃OD) δ; 0.88 (3H, t, J=7.4 Hz), 1.53 (2H, m), 1.85 (2H, m),1.98 (2H, m), 2.09–2.22 (4H, m), 2.49 (2H, m), 3.38 (2H, m), 3.51 (2H,m), 6.28 (1H, d, J=1.9 Hz), 6.87 (1H, dd, J=2.2, 8.9 Hz), 7.21 (1H, d,J=9.1 Hz).

EXAMPLE 505 Synthesis ofN-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)methanesulfonamide(a) Synthesis ofN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine

Sodium cyanoborohydride (484 mg, 7.70 mmol) and then acetic acid (440μl, 7.68 mmol) were added to a solution of the1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (335 mg, 1.54 mmol)obtained in Example 317, (e) and 8-propyl-8-azabicyclo[3.2.1]octan-3-one(300 mg, 1.85 mmol) in methanol (6 ml), and the resulting mixture wasstirred at room temperature for 1 day. Aqueous ammonia was addedthereto, followed by extraction with ethyl acetate. The extract solutionwas washed with a saturated aqueous sodium chloride solution, dried oversodium sulfate, and then distilled under reduced pressure to remove thesolvent. The residue was purified by a silica gel column chromatography(chloroform/methanol/triethylamine=100/1/5) to obtainN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine(413 mg, 73%).

¹H-NMR (CDCl₃) δ; 1.03 (3H, t, J=7.4 Hz), 1.56–1.89 (6H, m), 2.02–2.63(8H, m), 2.70–2.85 (4H, m), 3.70–3.83 (4H, m), 4.01 (1H, m), 5.65 (1H,dd, J=2.3, 9.2 Hz), 6.78 (1H, s), 6.83 (1H, dd, J=2.1, 8.9 Hz), 7.47(1H, d, J=8.8 Hz), 7.88 (1H, s).

(b) Synthesis ofN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-methanesulfonamide

Methanesulfonyl chloride (0.10 ml, 1.29 mmol) was added to a solution ofN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine(37 mg, 0.100 mmol) in pyridine (1 ml), and the resulting mixture wasstirred at room temperature for 3 days. The reaction solution was pouredinto a saturated aqueous sodium hydrogencarbonate solution, followed byextraction with ethyl acetate, and the extract solution was washed witha saturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent. Theresidue was purified by a preparative thin-layer chromatography(200×200×0.5 mm, 2 plates, eluent: chloroform/methanol=20/1) to obtainN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-methanesulfonamide(20 mg, 44%).

MS: m/z=447 (M+1)

(c) Synthesis ofN-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)methanesulfonamide

Trifluoroacetic acid (0.2 ml) was added to a solution ofN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-methanesulfonamide(19 mg, 0.0425 mmol) in dichloromethane (0.8 ml), and the resultingmixture was stirred at room temperature for 1.5 hours. The reactionsolution was poured into a saturated aqueous sodium hydrogencarbonatesolution and extracted with ethyl acetate, and the extract solution waswashed with a saturated aqueous sodium chloride solution, dried oversodium sulfate, and then distilled under reduced pressure to remove thesolvent. The residue was purified by a preparative thin-layerchromatography (200×200×0.5 mm, eluent: chloroform/methanol=9/1) toobtainN-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)methanesulfonamide(6 mg, 40%).

MS: m/z=363 (M+1)

EXAMPLE 506 Synthesis ofN-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)acetamide(a) Synthesis ofN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-acetamide

Acetic anhydride (0.50 m) was added to a solution of theN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine(37 mg, 0.100 mmol) obtained in Example 505, (a) in pyridine (1 ml), andthe resulting mixture was stirred at room temperature for 17 hours. Thereaction solution was poured into a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractsolution was washed with a saturated aqueous sodium chloride solution,dried over sodium sulfate, and then distilled under reduced pressure toremove the solvent. The residue was purified by a preparative thin-layerchromatography (200×200×0.5 mm, 2 plates, eluent:chloroform/methanol=6/1) to obtainN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-acetamide(35 mg, 85%).

MS: m/z=411 (M+1)

(b) Synthesis ofN-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)acetamide

Trifluoroacetic acid (0.2 ml) was added to a solution ofN-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-acetamide(35 mg, 0.0853 mmol) in dichloromethane (0.8 ml), and the resultingmixture was stirred at room temperature for 1.5 hours. The reactionsolution was poured into a saturated aqueous sodium hydrogencarbonatesolution and extracted with ethyl acetate. The extract solution waswashed with a saturated aqueous sodium chloride solution, dried oversodium sulfate, and then distilled under reduced pressure to remove thesolvent, wherebyN-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)acetamide(18 g, 64%) was obtained.

MS: m/z=327 (M+1)

EXAMPLE 507 Synthesis of 2-(1H-indazol-5-ylamino)benzamide

A 28%-aqueous ammonia solution (57.6 mg, 0.948 mmol),1-hydroxybenzotriazole (58 mg, 0.379 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (73 mg,0.379 mmol) were added in that order to a solution of2-(1H-indazol-5-ylamino)benzoic acid (80.0 mg, 0.316 mmol) inN,N-dimethylformamide (0.5 ml), and the resulting mixture was stirred atroom temperature for 20 hours. A 5% aqueous sodium hydrogencarbonatesolution was added to the reaction solution and stirred, followed byextraction with ethyl acetate/toluene/tetrahydrofuran (2/2/1). Theorganic phase was washed with a 5% aqueous sodium hydrogencarbonatesolution and then a 5%-aqueous sodium chloride solution and dried overanhydrous sodium sulfate. The organic phase dried was concentrated underreduced pressure and the resulting crude product was purified by asilica gel column chromatography (eluent: chloroform/methanol=50/1 to20/1) to obtain 2-(1H-indazol-5-ylamino)benzamide (66 mg, 83%).

¹H-NMR (CDCl₃) δ; 6.71 (1H, t-like, J=7.5 Hz), 7.10 (1H, d, J=8.6 Hz),7.23–7.31 (2H, m), 7.47–7.50 (2H, m), 7.60 (1H, s), 8.02 (1H, s), 9.60(1H, brs).

The following compounds of Example 508 to Example 513 were synthesizedby carrying out reaction according to the method described in Example507.

EXAMPLE 508 2-(1H-indazol-5-ylamino)-N-methylbenzamide

¹H-NMR (CDCl₃) δ; 3.01 (3H, d, J=5.0 Hz), 6.17 (1H, brs), 6.72 (1H,dt-like, J=1.3, 8.1 Hz), 7.14 (1H, dd, J=1.1, 8.4 Hz), 7.22 (1H,dt-like, J=1.3, 8.4 Hz), 7.28 (1H, dd, J=1.8, 8.8 Hz), 7.40 (1H, dd,J=1.5, 7.9 Hz), 7.46 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=1.8 Hz), 8.00(1H, d, J=0.92 Hz), 9.38 (1H, brs), 10.08 (1H, brs).

EXAMPLE 509 2-(1H-indazol-5-ylamino)-N-isobutylbenzamide

¹H-NMR (CDCl₃) δ; 0.99 (6H, d, J=6.6 Hz), 1.92 (1H, m), 3.28 (2H,t-like, J=6.4 Hz), 6.33 (1H, br t), 6.72 (1H, dt-like, J=1.3, 8.3 Hz),7.14 (1H, dd, J=1.1, 8.4 Hz), 7.20–7.27 (2H, m), 7.41–7.47 (2H, m), 7.56(1H, d, J=1.8 Hz), 8.01 (1H, d, J=0.7 Hz), 9.33 (1H, brs), 10.73 (1H,brs).

EXAMPLE 510 2-(1H-indazol-5-ylamino)-N-(2,2,2-trifluoroethyl)benzamide

¹H-NMR (CDCl₃) 67 ; 4.07–4.18 (2H, m), 6.44 (1H, m), 6.75 (1H, t-like,J=7.5 Hz), 7.11 (1H, d, J=8.4 Hz), 7.25–7.30 (2H, m), 7.45–7.50 (2H, m),7.58 (1H, d, J=1.3 Hz), 8.02 (1H, s), 9.27 (1H, brs), 10.13 (1H, brs).

EXAMPLE 511

N-[2-(dimethylamino)ethyl]-2-(1H-indazol-5-ylamino)benzamide

¹H-NMR (CDCl₃) δ; 2.29 (6H, s), 2.54 (2H, t, J=5.9 Hz), 3.51 (2H, m),6.73 (1H, t-like, J=7.5 Hz), 6.88 (1H, bm), 7.13 (1H, d, J=7.3 Hz), 7.22(1H, d, J=6.9 Hz), 7.29 (1H, dd, J=2.0, 8.9 Hz), 7.44–7.47 (2H, m), 7.57(1H, d, J=2.0 Hz), 8.00 (1H, s), 9.48 (1H, brs).

EXAMPLE 512

N-[2-(morpholin-4-ylcarbonyl)phenyl]-1H-indazol-5-amine

¹H-NMR (CDCl₃) δ; 3.70 (8H, m), 6.82 (1H, dt-like, J=7.7 Hz), 7.15–7.21(4H, m), 7.42 (1H, d, J=8.4 Hz), 7.47 (1H, d, J=1.8 Hz), 7.99 (1H, s),10.94 (1H, brs).

EXAMPLE 513 N-(1-benzylpiperidin-4-yl)-2-(1H-indazol-5-ylamino)benzamide

¹H-NMR (CDCl₃) δ; 1.57–1.61 (2H, m), 2.01–2.05 (2H, m), 2.16–2.23 (2H,m), 2.85–2.89 (2H, m), 3.53 (2H, s), 3.97 (1H, m), 6.04 (1H, bd, J=7.7Hz), 6.73 (1H, dt-like, J=1.1, 8.1 Hz), 7.14 (1H, dd, J=1.1, 8.4 Hz),7.21–7.33 (7H, m), 7.39 (1H, dd, J=1.3, 7.9 Hz), 7.45 (1H, d, J=8.8 Hz),7.56 (1H, d, J=2.0 Hz), 8.00 (1H, d, J=0.92 Hz), 9.35 1H, brs).

The following compound of Example 514 was synthesized by carrying outreaction according to the method described in Example 148, except forusing the N-(1-benzylpiperidin-4-yl)-2-(1H-indazol-5-ylamino)benzamidesynthesized in Example 513, as a starting material.

EXAMPLE 514 2-(1H-indazol-5-ylamino)-N-piperidin-4-ylbenzamide

¹H-NMR (CDCl₃) δ; 1.39–1.52 (2H, m), 2.05–2.09 (2H, m), 2.73–2.81 (2H,m), 3.12–3.16 (2H, m), 4.01–4.11 (1H, m), 6.08 (1H, bd, J=7.7 Hz), 6.73(1H, t-like, J=7.4 Hz), 7.15 (1H, d, J=8.4 Hz), 7.22–7.29 (2H, m), 7.41(1H, d, J=7.9 Hz), 7.46 (1H, d, J=9.0 Hz), 7.57 (1H, s), 8.00 (1H, s),9.36 (1H, brs).

EXAMPLE 515 Synthesis ofN-{2-[(4-benzylpiperazin-1-yl)carbonyl]phenyl}-1H-indazol-5-amine

To a solution of 2-(1H-indazol-5-ylamino)benzoic acid (102 mg, 0.402mmol) in N,N-dimethylformamide (0.5 ml) were added 1-benzylpiperazine(210 μl, 1.21 mmol), 1-hydroxybenzotriazole (74 mg, 0.484 mmol) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (94 mg,0.490 mmol) in that order, and the resulting mixture was stirred at roomtemperature for 21 hours. The mixture was dissolved in a 2N-aqueoussodium hydroxide solution (10 ml) and then extracted twice with ethylacetate/toluene/tetrahydrofuran (2/2/1, 10 ml). The extract solution waswashed with a saturated aqueous sodium chloride solution, dried oversodium sulfate, and then distilled under reduced pressure to remove thesolvent, whereby a crude product was obtained. The crude product waspurified by a silica gel column chromatography (eluent:chloroform/methanol=100/3) to obtainN-{2-[(4-benzylpiperazin-1-yl)carbonyl]phenyl}-1H-indazol-5-amine (162mg, 100%).

MS: m/z=412 (M+1)

The following compounds of Example 516 to Example 519 were synthesizedby carrying out reaction according to the method described in Example515.

EXAMPLE 516 N-(2-hydroxyethyl)-2-(1H-indazol-5-ylamino)benzamide

¹H-NMR (DMSO-d₆) 67 ; 3.31 (2H, m), 3.51 (2H, m), 4.72 (1H, m), 6.72(1H, t, J=7.4 Hz), 7.05 (1H, d, J=8.4 Hz), 7.16 (1H, d, J=9.0 Hz), 7.24(1H, t, J=7.7 Hz), 7.51 (2H, m), 7.65 (1H, d, J=7.9 Hz), 7.96 (1H, s),8.44 (1H, br), 9.67 (1H, s), 12.98 (1H, s).

EXAMPLE 517 1-[2-(1H-indazol-5-ylamino)benzoyl]piperidin-4-ol

MS: m/z=337 (M+1)

EXAMPLE 518 N,N-bis(2-hydroxyethyl)-2-(1H-indazol-5-ylamino)benzamide

¹H-NMR (CD₃OD) δ; 3.50–3.86 (8H, m), 6.87 (1H, t, J=7.4 Hz), 7.11 (1H,d, J=7.9 Hz), 7.19–7.27 (3H, m), 7.43–7.48 (2H, m), 7.91 (1H, s).

EXAMPLE 519trans-N-(4-hydroxycyclohexyl)-2-(1H-indazol-5-ylamino)benzamide

¹H-NMR (DMSO-d₆) δ; 1.18–1.46 (4H, m), 2.26 (4H, m), 3.39 (1H, m), 3.72(1H, m), 4.55 (1H, d, J=4.4 Hz), 6.72 (1H, t, J=7.2 Hz), 7.06 (1H, d,J=8.4 Hz), 7.15 (1H, d, J=8.5 Hz), 7.24 (1H, t, J=7.9 Hz), 7.49 (1H, s),7.51 (1H, d, J=9.0 Hz), 7.61 (1H, d, J=7.7 Hz), 7.96 (1H, s), 8.24 (1H,d, J=7.7 Hz), 9.60 (1H, s), 12.98 (1H, s).

EXAMPLE 520 Synthesis ofN-[2-(piperazin-1-ylcarbonyl)phenyl]-1H-indazol-5-amine

To a solution of theN-{2-[(4-benzylpiperazin-1-yl)carbonyl]phenyl}-1H-indazol-5-amine (127mg, 0.309 mmol) obtained in Example 515 in ethanol (5 ml) were added 10%Pd-C (20 mg) and ammonium formate (98 mg, 1.55 mmol), and the resultingmixture was heated under reflux for 2 hours. The solid was removed byfiltration using Celite, and the solvent was distilled off under reducedpressure. The residue was extracted with ethyl acetate, and the extractsolution was washed with a saturated aqueous sodium hydrogencarbonatesolution and then a saturated aqueous sodium chloride solution, driedover sodium sulfate, and then distilled under reduced pressure to removethe solvent, wherebyN-[2-(piperazin-1-ylcarbonyl)phenyl]-1H-indazol-5-amine (56 mg, 57%) wasobtained.

¹H-NMR (DMSO-d₆) δ; 2.61 (4H, m), 3.46 (4H, m), 6.84 (1H, t, J=7.3 Hz),7.05 (1H, d, J=8.3 Hz), 7.10–7.17 (2H, m), 7.21 (1H, t, J=7.7 Hz), 7.36(1H, s), 7.43 (1H, s), 7.44 (1H, d, J=8.8 Hz), 7.90 (1H, s), 12.89 (1H,s).

EXAMPLE 521 Synthesis of 4-(1H-indazole-5-ylamino)benzoic acid (a)tert-butyl 4-{1-(2-tetrahydropyranyl)-1H-indazol-5-ylamino}benzoate

In a two-necked flask the inner atmosphere of which had been replacedwith nitrogen were placed tert-butyl 4-bromobenzoate (2.57 mg, 1.00mmol), toluene (2 ml), 18-crown-6 (380 mg, 1.40 mmol), the1-(2-tetrahydropyranyl)-1H-indazol-5-amine (261 mg, 1.23 mmol) obtainedin Example 317, (e) and sodium tert-butoxide (135 mg, 1.40 mmol) in thatorder. After the inner atmosphere of the flask was replaced withnitrogen again, tris(dibenzylideneacetone)(chloroform) dipalladium(0)(52 mg, 0.050 mmol) and (S)-2,2′-bis(diphenylphophino)-1,1′-binaphthyl(94 mg, 0.151 mmol) were added. After the third replacement of the inneratmosphere of the flask with nitrogen, stirring was conducted at 80° C.for 8 hours. The resulting mixture was diluted with diethyl ether andthe solid was removed by filtration using Celite. Then, the solvent wasdistilled off under reduced pressure to obtain a crude product. Thecrude product was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate=3/1) to obtain tert-butyl4-{1-(2-tetrahydropyranyl)-1H-indazol-5-ylamino}benzoate (218 mg, 56%).

¹H-NMR (CDCl₃) δ; 1.57 (9H, s), 1.73 (3H, m), 2.11 (2H, m), 2.56 (1H,m), 3.77 (1H, m), 4.03 (1H, m), 5.72 (1H, dd, J=2.5, 9.5 Hz), 5.97 (1H,s), 6.86 (2H, d, J=8.8 Hz), 7.25 (1H, m), 7.51 (1H, s), 7.59 (1H, d,J=8.8 Hz), 7.85 (2H, d, J=8.8 Hz), 7.96 (1H, s).

(b) Synthesis of 4-(1H-indazole-5-ylamino)benzoic acid

Trifluoroacetic acid (5 ml) was added to a dichloromethane solution (5ml) of tert-butyl4-{1-(2-tetrahydropyranyl)-1H-indazol-5-ylamino}benzoate (205 mg, 0.521mmol), and the resulting mixture was stirred at room temperature for 3hours. The mixture was added dropwise to saturated aqueous sodiumhydrogencarbonate solution/ethyl acetate and then extracted with ethylacetate. The extract solution was washed with a saturated aqueous sodiumchloride solution, dried over sodium sulfate, and then distilled underreduced pressure to remove the solvent, whereby a crude product wasobtained. The crude product was washed by the addition of chloroformcontaining a small amount of methanol, and then was collected byfiltration to obtain 4-(1H-indazole-5-ylamino)benzoic acid (46 mg, 35%).

¹H-NMR (DMSO-d₆) δ; 6.92 (2H, d, J=8.6 Hz), 7.19 (1H, d, J=9.0 Hz), 7.52(2H, m), 7.73 (2H, d, J=8.6 Hz), 7.98 (1H, s), 8.59 (1H, s).

The following compound of Example 522 was synthesized by carrying outreaction according to the method described in Example 521.

EXAMPLE 522 3-(1H-indazole-5-ylamino)benzoic acid

¹H-NMR (DMSO-d₆) δ; 7.14–7.18 (2H, m), 7.28 (2H, m), 7.44 (1H, s),7.48–7.53 (2H, m), 7.95 (1H, s), 8.19 (1H, s).

EXAMPLE 523 Synthesis ofN-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1H-indazol-5-amine (a)Synthesis of 1,1-dioxidetetrahydro-2H-thiopyran-4-one (CVA-3878)

A solution of m-chloroperbenzoic acid (1.859 g, 10.8 mmol) in ethylacetate (13 ml) was added dropwise to a solution oftetrahydrothiopyran-4-one (0.500 g, 4.30 mmol) in ethyl acetate (5 ml)at such a rate that no reflux was caused by heat generation. Theresulting mixture was stirred overnight. The solution thus obtained wascooled on an ice bath and the solid precipitated was collected byfiltration. The precipitate on a filter was washed with cold ethylacetate and then dried under reduced pressure to obtain1,1-dioxidetetrahydro-2H-thiopyran-4-one (0.430 g, 67%).

(b) Synthesis ofN-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1H-indazol-5-amine(CVA-3879)

To a solution of 1,1-dioxidetetrahydro-2H-thiopyran-4-one (0.400 g, 2.70mmol) in 1,2-dichloroethane (10 ml) were added 5-aminoindazole (0.360 g,2.70 mmol) and sodium triacetoxyborohydride (0.801 g, 3.78 mmol), andthe resulting mixture was cooled on a water bath. Acetic acid (0.16 ml,2.8 mmol) was added thereto and stirred overnight. A saturated aqueoussodium hydrogencarbonate solution was added thereto, and the solidprecipitated was collected by filtration and the precipitate on a filterwas washed with water. The precipitate on the filter was suspended inmethanol and washed by stirring at 50° C. The suspension was cooled toroom temperature and the precipitate was collected by filtration. Theprecipitate on the filter was washed twice with diethyl ether and thendried under reduced pressure to obtainN-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1H-indazol-5-amine (0.355 g,50%).

Melting point: 254–256° C.

EXAMPLE 524 Synthesis ofN-(1-oxidetetrahydro-2H-thiopyran-4-yl)-1H-indazol-5-amine

The residue obtained by distilling off the solvent under the reducedpressure from the filtrate obtained after the washing with methanol inExample 523 was purified by a silica gel chromatography (eluent:chloroform/methanol=10/1) to obtainN-(1-oxidetetrahydro-2H-thiopyran-4-yl)-1H-indazol-5-amine (0.0648 g,10%).

Melting point: 220–222° C.

EXAMPLE 525 Synthesis ofN-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

A solution of iodine (0.488 g, 1.92 mmol) in hexamethyldisilane (0.560g, 3.83 mmol) was heated at 110° C. and stirred until the purplesolution became colorless. The solution was cooled to room temperature,followed by adding thereto a solution of the ethyl3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.200g, 0.637 mmol) obtained in Example 14 in 1,2-dichloroethane (6 ml), andthe resulting mixture was heated at 50° C. and stirred for 7 hours. Themixture was cooled to room temperature and methanol was added thereto toquench the mixture. Then, the solvent was distilled off under reducedpressure and a 1N-aqueous sodium hydroxide solution was added to theresidue. The solvent was distilled off under reduced pressure and theresidue was dried up and then purified by a silica gel chromatography(eluent: chloroform/methanol/30%-aqueous ammonia=100/10/1) to obtainN-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (0.0893 g, 58%).

Melting point: 236–238° C.

EXAMPLE 526 Synthesis of N-isopropyl-1H-indazol-5-amine

Acetone (25 μl, 0.340 mmol), sodium triacetoxyborohydride (83 mg, 0.392mmol) and acetic acid (18 μl, 0.314 mmol) were added in that order to asolution of 5-amino-1H-indazole (40 mg, 0.300 mmol) in1,2-dichloroethane (1 ml), and the resulting mixture was stirred at roomtemperature for 20 hours. The reaction was terminated by the use of asaturated aqueous sodium hydrogencarbonate solution (4 ml), followed byextraction with ethyl acetate. The solvent was distilled off underreduced pressure to obtain a crude product. The crude product waspurified by a silica gel column chromatography (eluent:chloroform/methanol=100/2) to obtain N-isopropyl-1H-indazol-5-amine (40mg, 76%).

MS: m/z=176 (M+1)

The following compounds of Example 527 to Example 541 were synthesizedby carrying out reaction according to the method described in Example526.

EXAMPLE 527 N-cyclobutyl-1H-indazol-5-amine

MS: m/z=188 (M+1)

EXAMPLE 528 N-cyclopentyl-1H-indazol-5-amine

MS: m/z=202 (M+1)

EXAMPLE 529 N-cycloheptyl-1H-indazol-5-amine

MS: m/z=230 (M+1)

EXAMPLE 530 N-(2,6-dimethylcyclohexyl)-1H-indazol-5-amine

MS: m/z=244 (M+1)

EXAMPLE 531 N-(2-methoxycyclohexyl)-1H-indazol-5-amine

MS: m/z=246 (M+1)

EXAMPLE 532 N-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-indazol-5-amine

MS: m/z=248 (M+1)

EXAMPLE 533 tert-butyl 4-(1H-indazol-5-ylamino)cyclohexylcarbamate

¹H-NMR (DMSO-d₆) δ; 1.10–1.30 (4H, m), 1.37 (9H, s), 1.77 (2H, m), 1.99(2H, m), 3.08 (1H, m), 3.23 (1H, m), 5.05 (1H, d, J=8.1 Hz), 6.63 (1H,s), 6.77 (1H, d, J=9.0 Hz), 7.23 (1H, d, J=8.4 Hz), 7.72 (1H, s), 12.54(1H, s).

EXAMPLE 534 N,N-dicyclopentyl-1H-indazol-5-amine

MS: m/z=270 (M+1)

EXAMPLE 535 N-(1-benzylpiperidin-3-yl)-1H-indazol-5-amine

MS: m/z=307 (M+1)

EXAMPLE 536 N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazol-5-amine

MS: m/z=243 (M+1)

EXAMPLE 537 N-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-indazol-5-amine

MS: m/z=273 (M+1)

EXAMPLE 538 N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazol-5-amine

MS: m/z=271 (M+1)

EXAMPLE 539 N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=257 (M+1)

EXAMPLE 5403-(1H-indazol-5-ylamino)-8-methyl-8-azabicyclo[3.2.1]octan-6-ol

MS: m/z=273 (M+1)

EXAMPLE 541 Ethyl3-[(1H-indazol-5-ylamino)methyl]-8-azabicyclo[3.2.1]octane-8-carbamate

MS: m/z=329 (M+1)

EXAMPLE 542 Synthesis of 2-(1H-indazol-5-ylamino)propane-1,3-diol

To a solution of the N-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-indazol-5-amine(23 mg, 0.0930 mmol) obtained in Example 532 in tetrahydrofuran (1 ml)was added 1N-hydrochloric acid (1 ml), and the resulting mixture wasstirred at room temperature for 1.5 hours. The reaction was terminatedby the use of a saturated aqueous sodium hydrogencarbonate solution,followed by extraction with ethyl acetate, whereby2-(1H-indazol-5-ylamino)propane-1,3-diol (16 mg, 84%) was obtained.

MS: m/z=208 (M+1)

EXAMPLE 543 Synthesis of 2-(1H-indazol-5-yl)cyclohexane-1,4-diamineditrifluoroacetate

Trifluoroacetic acid (1 ml) was added to a solution of the tert-butyl4-(1H-indazol-5-ylamino)cyclohexylcarbamate (25 mg, 0.0757 mmol)obtained in Example 533 in dichloromethane (1 ml), and the resultingmixture was stirred at room temperature for 4 hours. The solvent wasdistilled off under reduced pressure and the residue was washed withdiethyl ether and filtered to obtain2-(1H-indazol-5-yl)cyclohexane-1,4-diamine ditrifluoroacetate (32 mg,91%).

MS: m/z=231 (M+1)

EXAMPLE 544 Synthesis of N-piperidin-3-yl-1H-indazol-5-amine

To a solution of the N-(1-benzylpiperidin-3-yl)-1H-indazol-5-amine (463mg, 1.51 mmol) obtained in Example 535 in ethanol (10 ml) were added 10%Pd—C (50 mg) and then ammonium formate (952 mg, 15.1 mmol), and theresulting mixture was heated under reflux for 2 hours. The solid wasremoved by filtration using Celite, and the solvent was distilled offunder reduced pressure. Chloroform/aqueous ammonia was added to theresidue, followed by extraction with chloroform, and the extractsolution was washed with a saturated aqueous sodium chloride solution,dried over sodium sulfate, and then distilled under reduced pressure toremove the solvent, whereby N-piperidin-3-yl-1H-indazol-5-amine (241 mg,74%) was obtained.

MS: m/z=217 (M+1)

EXAMPLE 545 Synthesis ofN-(8-azabicyclo[3.2.1]oct-3-ylmethyl)-1H-indazol-5-amine

Iodine (599 mg, 2.36 mmol) was added to hexamethyldisilane (864 mg, 5.90mmol) and the resulting mixture was heated to 70° C. with stirring. Whenthe reaction solution became substantially colorless after violentreaction, it was cooled to room temperature. A solution of the ethyl3-[(1H-indazol-5-ylamino)methyl]-8-azabicyclo[3.2.1]octane-8-carbamate(386 mg, 1.18 mmol) obtained in Example 541 in dichloroethane (8 ml) wasadded thereto, and the resulting mixture was stirred at 50° C. for 5hours. The reaction was terminated by adding methanol (4 ml) underice-cooling, and then the solvent was distilled off under reducedpressure. Chloroform/aqueous ammonia was added to the residue, followedby extraction with chloroform, and the extract solution was washed witha saturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent, wherebyN-(8-azabicyclo[3.2.1]oct-3-ylmethyl)-1H-indazol-5-amine (258 mg, 85%)was obtained.

MS: m/z=257 (M+1)

EXAMPLE 546 Synthesis ofN-(8-(2-phenoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

Potassium carbonate (52 mg, 0.376 mmol) and then 2-phenoxyethyl bromide(38 mg, 0.189 mmol) were added to a suspension of theN-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (30 mg, 0.124 mmol)obtained in Example 525 in dimethylformamide (1 ml), and the resultingmixture was stirred at room temperature for 20 hours. After the solidwas removed by filtration, the dimethylformamide was distilled off underreduced pressure as an azeotrope with toluene to obtain a crude product.The crude product was purified by a silica gel column chromatography(eluent: chloroform/methanol/triethylamine=20/1/1) to obtainN-(8-(2-phenoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine(40 mg, 89%).

MS: m/z=377 (M+1)

The following compounds of Example 547 to Example 567 were synthesizedby carrying out reaction according to the method described in Example546.

EXAMPLE 547 N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=285 (M+1)

EXAMPLE 548N-(8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=285 (M+1)

EXAMPLE 549N-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=299 (M+1)

EXAMPLE 550N-[8-(cyclobutylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=311 (M+1)

EXAMPLE 551N-[8-(cyclohexylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=339 (M+1)

EXAMPLE 552N-[8-(2-phenylethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=347 (M+1)

EXAMPLE 5532-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]ethanol

MS: m/z=287 (M+1)

EXAMPLE 5543-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]propan-1-ol

MS: m/z=301 (M+1)

EXAMPLE 555N-[8-(2-methoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=301 (M+1)

EXAMPLE 556N-[8-(tetrahydro-2H-pyran-2-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=341 (M+1)

EXAMPLE 5573-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]propanenitrile

MS: m/z=296 (M+1)

EXAMPLE 5582-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]acetamide

MS: m/z=300 (M+1)

EXAMPLE 559 N-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=271 (M+1)

EXAMPLE 560 N-(8-allyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=283 (M+1)

EXAMPLE 561N-(8-but-3-enyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z 297 (M+1)

EXAMPLE 562N-[8-(3-methylbut-2-enyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=311 (M+1)

EXAMPLE 563N-[8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=297 (M+1)

EXAMPLE 5641-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]propan-2-ol

MS: m/z=301 (M+1)

EXAMPLE 565[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]acetonitrile

MS: m/z=282 (M+1)

EXAMPLE 5664-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]butanenitrile

MS: m/z=310 (M+1)

EXAMPLE 567N-[8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=325 (M+1)

EXAMPLE 568 Synthesis ofN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

Benzaldehyde (37 μl, 0.364 mmol) and sodium triacetoxyborohydride (127mg, 0.599 mmol) were added to a suspension of theN-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (73 mg, 0.301 mmol)obtained in Example 525 in dichloromethane (1 ml), and the resultingmixture was stirred at room temperature for 25 hours. The reaction wasterminated by the addition of a saturated aqueous sodiumhydrogencarbonate solution, followed by extraction with ethyl acetate.The extract solution was washed with a saturated aqueous sodium chloridesolution, dried over sodium sulfate, and then distilled under reducedpressure to remove the solvent, whereby a crude product was obtained.The crude product was washed with cold methanol and collected byfiltration to obtainN-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (52 mg,52%).

¹H-NMR (DMSO-d₆) δ; 1.68 (2H, m), 2.01 (6H, m), 3.06 (2H, m), 3.48 (1H,m), 3.50 (2H, s), 5.21 (1H, br), 6.47 (1H, s), 6.85 (1H, d, J=9.2 Hz),7.18–7.40 (6H, m), 7.73 (1H, s), 12.55 (1H, s).

The following compounds of Example 569 to Example 572 were synthesizedby carrying out reaction according to the method described in Example568.

EXAMPLE 569N-(8-cyclobutyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=297 (M+1)

EXAMPLE 570N-(8-cyclopentyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=311 (M+1)

EXAMPLE 571N-(8-cyclohexyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=325 (M+1)

EXAMPLE 572N-(8-tetrahydro-2H-pyran-4-yl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine

MS: m/z=327 (M+1)

EXAMPLE 573 Synthesis of2-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]-2-oxoethanol

Hydroxyacetic acid (32 mg, 0.421 mmol), 1-hydroxybenzotriazole (76 mg,0.496 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (95 mg, 0.496 mmol) were added in that order to asuspension of the N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine(100 mg, 0.413 mmol) obtained in Example 525 in dimethylformamide (1ml), and the resulting mixture was stirred at room temperature for 23hours. The reaction mixture was poured into a saturated aqueous sodiumhydrogencarbonate solution to terminate the reaction, and was extractedtwice with ethyl acetate. The extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent, wherebya crude product was obtained. The crude product was purified by apreparative thin-layer chromatography (200×200×0.5 mm, 4 plates, eluent:chloroform/methanol=15/1) to obtain2-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]-2-oxoethanol(13 mg, 11%).

MS: m/z=301 (M+1)

The following compounds of Example 574 and Example 575 were synthesizedby carrying out reaction according to the method described in Example573.

EXAMPLE 574N-[8-(2-methoxyacetyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=315 (M+1)

EXAMPLE 575N-[8-(2-phenoxyacetyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-indazol-5-amine

MS: m/z=377 (M+1)

EXAMPLE 576 Synthesis ofN-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazol-5-amine dihydrochloride

To a solution of the N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazol-5-amine(178 mg, 0.75 mmol) obtained in Example 536 in methanol (5 ml) was added1N-hydrochloric acid/diethyl ether (3 ml), and the resulting mixture wasstirred at room temperature for 1 hour. After diethyl ether (15 ml) wasadded thereto, the solid formed was collected by filtration, washed withdiethyl ether and then dried to obtainN-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazol-5-amine dihydrochloride (210mg, 91%).

Melting point: 184–188° C.

The following compound of Example 577 was synthesized by carrying outreaction according to the method described in Example 576, except forusing the2-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]ethanol obtainedin Example 553, as a starting material.

EXAMPLE 5772-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]ethanoldihydrochloride

Melting point: 154–157° C.

The following compound of Example 578 was synthesized by carrying outreaction according to the method described in Example 576, except forusing the N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amineobtained in Example 547, as a starting material.

EXAMPLE 578 N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-aminedihydrochloride

Melting point: 198–203° C.

The following compounds of Examples 579 and 580 were synthesized bycarrying out reactions according to the methods described in Example372, (b) and Example 377, except for using the 4-methoxy-1H-indazol-5-olobtained in Example 469, as a starting material.

EXAMPLE 579 5-(4-Azepanyloxy)-4-methoxy-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.57 (1H, m), 1.83–2.02 (5H, m), 2.85–3.00 (3H, m),3.14 (1H, m), 4.04 (3H, s), 4.33 (1H, m), 7.10 (2H, s), 8.15 (1H, s),13.00 (1H, brs)

EXAMPLE 580 4-Methoxy-5-(4-piperidinyloxy)-1H-indazole monohydrochloride

¹H-NMR (DMSO-d₆) δ; 1.85 (2H, m), 1.98 (2H, m), 3.03 (2H, m), 3.24 (2H,m), 4.08 (3H, s), 4.33 (1H, m), 7.12 (1H, d, J=8.8 Hz), 7.14 (1H, d,J=8.8 Hz), 8.19 (1H, s), 8.82 (2H, brs).

The following compound of Example 581 was synthesized by carrying outreactions according to the methods described in Example 372, (b),Example 377 and Example 327, except for using the4-methoxy-1H-indazol-5-ol obtained in Example 469, as a startingmaterial.

EXAMPLE 581 4-Methoxy-5-(3-piperidinyloxy)-1H-indazole monohydrochloride

¹H-NMR (DMSO-d₆) δ; 1.64 (1H, m), 1.80 (2H, m), 1.98 (1H, m), 3.04 (2H,m), 3.25 (2H, m), 4.12 (3H, s), 4.30 (1H, m), 7.12 (1H, d, J=8.8 Hz),7.18 (1H, d, J=8.8 Hz), 8.24 (1H, s), 8.60 (1H, brs), 9.02 (1H, brs).

The following compounds of Example 582 and Example 583 were synthesizedby carrying out reaction according to the method described in Example385, except for using the 4-methoxy-1H-indazol-5-ol obtained in Example469, as a starting material.

EXAMPLE 582 trans-3-[(4-Methoxy-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 1.11 (1H, m), 1.30–1.56 (5H, m), 1.65 (3H, m), 1.96(1H, m), 3.04 (1H, m), 4.02 (3H, s), 4.46 (1H, m), 7.09 (2H, s), 8.10(1H, s), 12.95 (1H, brs).

EXAMPLE 583 cis-3-[(4-Methoxy-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 0.89 (1H, m), 1.04–1.23 (3H, m), 1.45 (2H, brs),1.68 (2H, m), 1.93 (1H, m), 2.08 (1H, m), 2.51 (1H, m), 3.97 (1H, m),4.03 (3H, s), 7.08 (2H, s), 8.11 (1H, s), 12.96 (1H, brs).

The following compounds of Example 584 and Example 585 were synthesizedby carrying out reactions according to the methods described in Example385 and Example 327, except for using the 4-methoxy-1H-indazol-5-olobtained in Example 469, as a starting material.

EXAMPLE 584 trans-4-[(4-Methoxy-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

¹H-NMR (DMSO-d₆) δ; 1.30–1.53 (4H, m), 1.94–2.06 (4H, m), 3.04 (1H, m),3.97 (1H, m), 4.04 (3H, s), 7.09 (1H, d, J=8.8 Hz), 7.10 (1H, d, J=8.8Hz), 7.92 (3H, brs), 8.13 (1H, s).

EXAMPLE 585 cis-4-[(4-Methoxy-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

¹H-NMR (DMSO-d₆) δ; 1.55 (2H, m), 1.76–1.84 (4H, m), 1.90–1.95 (2H, m),3.07 (1H, m), 4.07 (3H, s), 4.30 (1H, m), 7.11 (2H, s), 7.92 (3H, brs),8.15 (1H, s).

The following compounds of Example 586 to Example 588 were synthesizedby carrying out reactions according to the methods described in Example365 and Example 381, except for using the4-(trifluoromethyl)-1H-indazol-5-ol obtained in Example 474, as astarting material.

EXAMPLE 586trans-4-{[4-(Trifluoromethyl)-1H-indazol-5-yl]oxy}cyclohexanamine

MS: m/z=300 (M+1)

EXAMPLE 587cis-3-{[4-(Trifluoromethyl)-1H-indazol-5-yl]oxy}cyclohexanamine

MS: m/z=300 (M+1)

EXAMPLE 588cis-4-{[4-(Trifluoromethyl)-1H-indazol-5-yl]oxy}cyclohexanamine

MS: m/z=300 (M+1)

EXAMPLE 589 Synthesis of 5-(azepan-3-yloxy)-4-methyl-1H-indazole (a)Synthesis of Ethyl 5-[benzyl(2-ethoxy-2-oxoethyl)amino]pentanoate

Under a nitrogen atmosphere, triethylamine (1.73 ml, 0.01243 mol) andethyl 5-bromovalerate (1.72 ml, 0.0109 mol) were added to a solution ofN-benzylglycine ethyl ester (2.0 g, 0.0103 mol) in acetonitrile (40 ml)at room temperature, and the resulting mixture was heated at 60° C.After 1 hour, the mixture was refluxed. After 9 hours, the mixture wasconcentrated under reduced pressure, and the resulting residue wasextracted with water (200 ml) and ethyl acetate (200 ml×2) and theorganic layer was dried over anhydrous magnesium sulfate. The organiclayer dried was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate) to obtain ethyl5-[benzyl(2-ethoxy-2-oxoethyl)amino]pentanoate (1.2473 g, 37%).

(b) Synthesis of ethyl 1-benzyl-3-oxoazepane-2-carboxylate and ethyl1-benzyl-3-oxoazepane-4-carboxylate

Under a nitrogen atmosphere, a 21% wt. sodium ethoxide-ethanol solution(1.23 ml, 3.31 mmol) was added to toluene (100 ml) at room temperature,and the resulting mixture was refluxed by the use of a Dean-Stark trap.A solution of ethyl 5-[benzyl(2-ethoxy-2-oxoethyl)amino]pentanoate(965.9 mg, 3.01 mmol) in toluene (50 ml) was added dropwise thereto overa period of 1.5 hours. After 3 hours, a 21% wt. sodium ethoxide-ethanolsolution (1.23 ml, 3.31 mmol) was further added thereto. After another 1hour, the toluene (30 ml) was distilled off with heating. After 5 hours,the reaction solution was poured into water (200 ml) and extracted withethyl acetate (100 ml×2), and the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain ethyl1-benzyl-3-oxoazepane-4-carboxylate (158.5 mg, 19%) and ethyl1-benzyl-3-oxoazepane-2-carboxylate (213.8 mg, content=about 75%).

(c) Synthesis of 1-benzylazepan-3-one

Under a nitrogen atmosphere, a 75%-aqueous sulfuric acid solution (2 ml)was added to a solution of ethyl 1-benzyl-3-oxoazepane-4-carboxylate(150 mg, 0.545 mmol) in ethanol (1 ml) at room temperature, and theresulting mixture was heated to 120° C. After 3 hours, completion of thereaction was confirmed and the resulting mixture was cooled. On theother hand, under a nitrogen atmosphere, a 75%-aqueous sulfuric acidsolution (2 ml) was added to a solution of the mixture containing ethyl1-benzyl-3-oxoazepane-2-carboxylate (200 mg, content=about 75%) inethanol (1 ml) at room temperature, and the resulting mixture was heatedto 120° C. After 12 hours, completion of the reaction was confirmed andthe temperature was lowered. The reaction solution was combined withthat obtained above, and the combined reaction solution was poured ontoice and adjusted to pH 8 with a 2M-aqueous sodium hydroxide solution.The combined reaction solution thus treated was extracted with ethylacetate (50 ml×2) and the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain1-benzylazepan-3-one (118.1 mg, 53%).

(d) Synthesis of 1-benzylazepan-3-ol

Under a nitrogen atmosphere, lithium aluminum hydride (1.4 mg, 0.0369mmol) was added to a solution of 1-benzylazepan-3-one (15 mg, 0.0738mmol) in diethyl ether (1 ml) at 0° C., and the resulting mixture washeated to room temperature. After 30 minutes, water, a 2M-aqueous sodiumhydroxide solution and water were added in that order to the reactionsolution. The resulting mixture was filtered by the use of Celite, andthe filtrate was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:chloroform/methanol) to obtain 1-benzylazepan-3-ol (16.2 mg, 100%).

(e) Synthesis of tert-butyl 3-hydroxyazepane-1-carboxylate

Under a nitrogen atmosphere, 10%-Pd/C 50% wet (500 mg) and ammoniumformate (2.0 g) were added to a solution of 1-benzylazepan-3-ol (1.072g, 5.22 mmol) in ethanol (40 ml) at room temperature, and the resultingmixture was refluxed. After 1 hour, the reaction solution was filteredby the use of Celite and the resulting filtrate was concentrated underreduced pressure. The concentrate was dried under reduced pressure andto a solution of the resulting residue in dichloromethane (25 ml) wasadded di-t-butyl dicarbonate (1.32 ml, 5.74 mmol) at 0° C. After 30minutes, the mixture thus obtained was warmed up to room temperature.After 2.5 hours, the mixture was poured into water (100 ml) andextracted with chloroform (50 ml×2), and then the organic layer wasdried over anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain tert-butyl 3-hydroxyazepane-1-carboxylate (946.7 mg,84%).

(f) Synthesis of 5-(azepan-3-yloxy)-4-methyl-1H-indazole

Under a nitrogen atmosphere, triphenylphosphine (146 mg, 0.559 mmol),tert-butyl 3-hydroxyazepane-1-carboxylate (100 mg, 0.466 mmol) anddiisopropyl azodicarboxylate (101 μl, 0.512 mmol) were added at 0° C. toa solution of the 4-methyl-1H-indazol-5-ol (69 mg, 0.466 mmol) obtainedin Example 402 in tetrahydrofuran (4 ml). After 30 minutes, the mixturethus obtained was warmed up to room temperature and stirred overnight.The reaction solution was concentrated under reduced pressure, and theresulting residue was diluted with chloroform and washed with a1M-aqueous sodium hydroxide solution. After the aqueous layer wasre-extracted with chloroform, the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate). The oil thusobtained was dissolved in methanol (2 ml) at room temperature, and4N-hydrochloric acid-dioxane (2 ml) was added thereto. After 1 hour, themixture thus obtained was concentrated under reduced pressure and theresulting residue was dissolved in methanol (5 ml). The resultingsolution was adjusted to pH 10 by dropwise addition of a 2M-aqueoussodium hydroxide solution. The solution adjusted was concentrated underreduced pressure and the resulting residue was re-dissolved in methanol(5 ml). Silica gel (1 g) was added thereto and the resulting mixture wasconcentrated under reduced pressure and then dried. The resulting solidwas purified by a silica gel column chromatography (eluent:chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain5-(azepan-3-yloxy)-4-methyl-1H-indazole (45.1 mg, 39%).

IR (neat) cm⁻¹; 3220, 2941, 1512, 1217, 715.

EXAMPLE 590 Synthesis oftrans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (a)Synthesis of cis-3-amino-4,4-dimethylcyclohexanol hydrochloride

Sodium borohydride (4.2 mmol, 160 mg) was added in small portions to asolution of 3-azide-4,4-dimethylcyclohexanone (700 mg, 4.2 mmol) inmethanol (10 ml) at room temperature, and the resulting mixture wasstirred for 20 minutes. The reaction mixture was diluted with ethylacetate (100 ml) and washed with a saturated aqueous sodium chloridesolution (100 ml×2). The organic layer was dried over anhydrousmagnesium sulfate and the insoluble material was filtered off. Then, thefiltrate was concentrated under reduced pressure to a total volume ofabout 10 ml. After the rsulting residue was diluted with methanol (30ml), 10% palladium carbon (50% wet, 200 mg) was added thereto and theresulting mixture was stirred at room temperature for 1 hour under ahydrogen atmosphere. After the insoluble material was removed byfiltration using Celite, the filtrate was concentrated under reducedpressure and the resulting residue was converted to its hydrochloridewith a 1N-HCl ether solution to obtaincis-3-amino-4,4-dimethylcyclohexanol hydrochloride (720 mg, 95%,containing about 15% of trans isomer) as white powder.

¹H-NMR (DMSO-d₆) δ; 0.85 (3H, s), 0.98 (3H, s), 1.05–1.80 (5H, m),1.90–2.00 (1H, m), 2.79 (1H, m), 3.40 (1H, m), 4.80 (1H, brs), 7.99 (3H,m).

(b) Synthesis ofcis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione

Acetonitrile (5 ml), potassium carbonate (3.1 mmol, 423 mg) andN-carboethoxyphthalimide (3.1 mmol, 670 mg) were added to a solution ofcis-3-amino-4,4-dimethylcyclohexanol hydrochloride (500 mg, 2.8 mmol) inwater (10 ml), and the resulting mixture was stirred as it was for 2hours. The crystals precipitated were collected by filtration and thenrecrystallized from chloroform-diethyl ether to obtaincis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (400mg, 53%, containing about 10% of trans isomer) as white powder.

¹H-NMR (DMSO-d₆) δ; 0.90 (3H, s), 1.05 (3H, s), 1.30–1.75 (5H, m),1.80–1.95 (2H, m), 2.84 (1H, q, J=12.5 Hz), 3.69 (1H, m), 4.04 (1H, dd,J=3.1, 13.0 Hz), 7.65–7.90 (4H, m).

(c) Synthesis oftrans-2-{2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione

To a solution of the 4-methyl-1H-indazol-5-ol (500 mg, 1.83 mmol)obtained in Example 402 in toluene (8 ml) were addedcis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (400mg, 1.5 mmol) and cyanomethylenetri-n-butylphosphorane (494 mg, 2.1mmol) at room temperature, and the resulting mixture was heated to 100°C. After stirring for 7 hours, the reaction solution was concentratedunder reduced pressure and the resulting residue was dissolved inchloroform and washed with a 1M-aqueous sodium hydroxide solution.Extraction with chloroform was carried out again and the organic layerwas dried over anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtaintrans-2-{2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(360 mg, 61%, containing about 10% of cis isomer).

¹H-NMR (CDCl₃) δ; 1.00 (3H, s), 1.08 (3H, s), 1.35–1.50 (1H, m),1.70–2.20 (4H, m), 2.59 (3H, s), 3.05 (1H, dt, J=2.6, 13.5 Hz),4.65–4.78 (2H, m), 7.09 (1H, d, J=9.0 Hz), 7.24 (1H, d, J=9.0 Hz),7.67–7.75 (2H, m), 7.76–7.85 (2H, m), 8.03 (1H, d, J=1.1 Hz), 10.04 (1H,brs)

(d) Synthesis oftrans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Totrans-2-{2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dionewas added 30%-methylamine/ethanol (10 ml) at room temperature, and theresulting mixture was refluxed for 8 hours. The reaction solution wasconcentrated under reduced pressure at room temperature and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform→chloroform/methanol/(1%-aqueous ammonia)=20/1) toobtaintrans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (143mg, 60%, containing about 10% of cis isomer).

¹H-NMR (DMSO-d₆) δ; 0.79 (3H, s), 0.94 (3H, s), 1.10–1.90 (6H, m), 2.39(3H, s), 2.74 (1H, dd, J=4.1, 10.4 Hz), 4.49 (1H, m), 7.09 (1H, d, J=8.8Hz), 7.27 (1H, d, J=8.8 Hz), 7.99 (1H, d, J=0.9 Hz), 12.85 (1H, brs).

EXAMPLE 591 Synthesis ofcis-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (a)trans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4-dimethylcyclohexyl4-nitrobenzoate

To a solution of thecis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (500mg, 1.83 mmol) obtained in Example 590 in tetrahydrofuran (10 ml) wereadded 4-nitrobenzoic acid (321 mg, 1.05 mmol), triphenylphosphine (576mg, 2.20 mmol) and a 40%-diethyl azodicarboxylate/toluene solution (1.00ml, 2.20 mmol) at 3° C., and stirred overnight at room temperature. Thereaction solution was concentrated and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtaintrans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4-dimethylcyclohexyl4-nitrobenzoate (509 mg, 66%).

¹H-NMR (CDCl₃) δ; 0.90 (3H, s), 1.05 (3H, s), 1.30–2.00 (6H, m), 2.85(1H, q, J=13.4 Hz), 3.69 (1H, m), 4.05 (1H, dd, J=3.5, 13.4 Hz),7.66–7.75 (2H, m), 7.78–7.87 (2H, m).

(b) Synthesis oftrans-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione

To a suspension oftrans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4-dimethylcyclohexyl4-nitrobenzoate (420 mg, 1.00 mmol) in a mixture of methanol (0.10 ml)and tetrahydrofuran (10 ml) was added 28%-sodium methoxide (0.24 ml,1.00 mmol) at 3° C., and stirred at 0° C. for 30 minutes and then atroom temperature for 35 minutes. The reaction solution was adjusted topH 4 with a 0.5M-aqueous potassium hydrogensulfate solution and thendistilled under reduced pressure to remove the solvent. The residue wasadded to water and extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate and distilled under reducedpressure to remove the solvent, and the resulting residue was purifiedby a silica gel column chromatography (hexane/ethyl acetate=2/1) toobtaintrans-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione(231 mg, 85%).

¹H-NMR (CDCl₃) δ; 0.93 (3H, s), 1.02 (3H, s), 1.25–1.40 (2H, m),1.55–2.00 (4H, m), 3.04 (1H, dt, J=2.9, 13.7 Hz), 4.31 (1H, m), 4.55(1H, dd, J=3.5, 13.4 Hz), 7.67–7.75 (2H, m), 7.76–7.87 (2H, m).

(c)cis-2-{2,2-Dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 590, (c)

¹H-NMR (CDCl₃) δ; 0.92 (3H, s), 1.12 (3H, s), 1.20–2.20 (5H, m), 2.51(3H, s), 3.04 (1H, m), 4.00–4.15 (2H, m), 7.11 (1H, d, J=8.8 Hz), 7.24(1H, d, J=8.8 Hz), 7.67–7.75 (2H, m), 7.76–7.85 (2H, m), 8.02 (1H, d,J=0.9 Hz).

(d) Synthesis oftrans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 590, (d).

Melting point: 170–171° C.

¹H-NMR (DMSO-d₆) δ; 0.79 (3H, s), 0.87 (3H, s), 1.00–1.60 (6H, m),1.70–1.95 (2H, m), 2.30 (1H, dd, J=3.7, 11.9 Hz), 2.37 (3H, s), 3.98(1H, m), 7.10 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=8.8 Hz), 7.99 (1H, d,J=0.6 Hz), 12.87 (1H, brs).

EXAMPLE 592 Synthesis of1-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-methanaminehydrochloride (a) Synthesis of methyl4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate

To a solution of methyl 4-hydroxycyclohexane-carboxylate (a cis/transmixture, 5.00 g, 31.6 mmol) and imidazole (4.30 g, 63.2 mmol) indimethylformamide (20 ml) was added t-butyldimethylsilyl chloride (5.72g, 37.9 mmol) at room temperature, and stirred at the same temperaturefor 5 hours. After completion of the reaction, an ethyl acetate/toluene(1/1) solution and water were added thereto, and the organic layer wascollected, dried over sodium sulfate and distilled under reducedpressure to remove the solvent, whereby methyl4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexane-carboxylate (8.66 g, 100%)was obtained.

(b) Synthesis of (4-{[tert-butyl(dimethyl)silyl]-oxy}cyclohexyl)methanol

Lithium aluminum hydride (696 mg, 18.4 mmol) was added to atetrahydrofuran solution (25 ml) of methyl4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (2.50 g, 9.18mmol) under ice-cooling. The resulting mixture was warmed up to roomtemperature and then stirred overnight. After completion of thereaction, water and a 15% aqueous sodium hydroxide solution were addedthereto and stirred. The solid formed was removed by filtration, and thesolvent was distilled off under reduced pressure to obtain a crudeproduct. The crude product was purified by a silica gel columnchromatography (hexane-ethyl acetate=1:1) to obtain(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methanol (2.08 g, 93%).

(c) Synthesis of2-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl]-1H-isoindazole-1,3(2H)-dione

At room temperature, a solution of(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methanol (1.00 g, 4.09mmol), triphenylphosphine (1.18 g, 4.50 mmol) and phthalimide (722 mg,4.91 mmol) in tetrahydrofuran (15 ml) were stirred for 30 minutes.Diethyl diazodicarboxylate (a 40% toluene solution, 2.20 g, 4.91 mmol)was slowly added to the reaction solution, and the resulting mixture wasstirred at room temperature for 5 hours. The solvent was distilled offunder reduced pressure and the residue was purified by a silica gelcolumn chromatography (hexane/ethyl acetate=4:1) to obtain2-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl]-1H-isoindazole-1,3(2H)-dione(1.60 g, 100%).

(d) Synthesis of2-[4-(hydroxycyclohexyl)methyl]-1H-isoindazole-1,3(2H)-dione

Trifluoroacetic acid (1 ml) was added to a solution of2-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl]-1H-isoindazole-1,3(2H)-dione(1.60 g, 4.09 mmol) in tetrahydrofuran/water (1:1, 10 ml), and theresulting mixture was stirred at room temperature for 6 hours. Ethylacetate/5% aqueous sodium chloride solution was added to the reactionsolution, followed by extraction with ethyl acetate, and the extractsolution was dried over sodium sulfate and distilled under reducedpressure to remove the solvent. The residue was purified by a silica gelcolumn chromatography (hexane/ethyl acetate=2:1-1:1) to obtain2-[4-(hydroxycyclohexyl)methyl]-1H-isoindazole-1,3(2H)-dione (0.70 g,61%).

(e) Synthesis of2-({4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methyl)-1H-isoindazole-1,3(2H)-dione

Cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol) and the4-methyl-1H-indazol-5-ol (306 mg, 2.07 mmol) obtained in Example 402were added to a toluene solution (10 ml) of2-[4-(hydroxycyclohexyl)methyl]-1H-isoindazole-1,3(2H)-dione (358 mg,1.38 mmol) at room temperature, and the resulting mixture was heatedunder reflux for 2 hours. The reaction solution was cooled to roomtemperature and distilled under reduced pressure to remove the solvent.Chloroform and a 5% aqueous sodium hydroxide solution were added to theresidue, and the organic layer was collected and then dried over sodiumsulfate. The solvent was distilled off under reduced pressure to obtaina crude product2-({4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methyl)-1H-isoindazole-1,3(2H)-dione(1.43 g).

(f) Synthesis of1-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-methanamine

A 30% methylamine-ethanol solution (10 g) was added to2-({4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methyl)-1H-isoindazole-1,3(2H)-dione(358 mg, 1.38 mmol) at room temperature, and the resulting mixture washeated under reflux for 2 hours. The reaction solution was cooled toroom temperature and distilled under reduced pressure to remove thesolvent. The residue was purified by a silica gel column chromatography(chloroform/methanol/triethylamine=10:1:1) to obtain1-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-methanamine (1.50 mg,42%).

(g) Synthesis of1-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-methanaminehydrochloride

A 1N-hydrochloric acid-diethyl ether solution (0.70 ml, 0.70 mmol) wasadded to a solution of1-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-methanamine (150 mg,0.578 mmol) in methanol (2 ml) at room temperature and stirred at thesame temperature for 30 minutes. The solvent was distilled off underreduced pressure, and the residue was solidified with isopropylalcohol-diisopropyl ether, filtered and then dried to obtain1-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-methanaminehydrochloride (148 mg, 87%).

IR (neat) cm⁻¹; 2927, 1508, 1267, 1227, 1084, 945.

EXAMPLE 593 Synthesis ofcis-4-[(4-chloro-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride (a)Synthesis of cis-4-[(4-chloro-1H-indazol-5-yl)oxy]cyclohexanamine

Under a nitrogen atmosphere, triphenylphosphine (280 mg, 1.07 mmol), thetrans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (218 mg, 0.890mmol) obtained in Example 323, (a) and diisopropyl azodicarboxylate (193μl, 0.979 mmol) were added to a solution of the 4-chloro-1H-indazol-5-ol(150 mg, 0.890 mmol) obtained in Example 468 in tetrahydrofuran (6 ml)at 0° C. After 30 minutes, the mixture thus obtained was warmed up toroom temperature and stirred overnight. The reaction solution wasconcentrated under reduced pressure, and the resulting residue wasdiluted with chloroform (20 ml) and then washed with a 1M-aqueous sodiumhydroxide solution (10 ml). After the aqueous layer was re-extractedwith chloroform (10 ml), the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate). To the resultingoil was added a 30%-methylamine-ethanol solution at room temperature,and the resulting mixture was refluxed. After 4 hours, the mixture wasconcentrated under reduced pressure at room temperature, and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia))to obtain cis-4-[(4-chloro-1H-indazol-5-yl)oxy]cyclohexanamine (83.6 mg,35%).

(b) Synthesis of cis-4-[(4-chloro-1H-indazol-5-yl)oxy]cyclohexanaminehydrochloride

Under a nitrogen atmosphere, methanol (1 drop) was added to a suspensionof cis-4-[(4-chloro-1H-indazol-5-yl)oxy]cyclohexanamine (54.2 mg, 0.204mmol) in acetonitrile (4 ml) at room temperature to effect dissolution,and 1M-hydrochloric acid-diethyl ether (224 μl, 0.224 mmol) was addeddropwise thereto. After 1 hour, diethyl ether (10 ml) was added to thereaction suspension and the resulting mixture was filtered. Then, theprecipitate was dried under pressure to obtaincis-4-[(4-chloro-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride (57.8mg, 94%).

IR (neat) cm⁻¹; 2939, 1504, 1240, 939, 796.

EXAMPLE 594 Synthesis of 5-(azepin-4-yloxy)-4-chloro-1H-indazole

Under a nitrogen atmosphere, triphenylphosphine (280 mg, 1.07 mmol), thetert-butyl 4-hydroxyazepane-1-carboxylate (192 mg, 0.890 mmol) obtainedin Example 322, (c) and diisopropyl azodicarboxylate (193 μl, 0.979mmol) were added at 0° C. to a solution of the 4-chloro-1H-indazol-5-ol(150 mg, 0.890 mmol) obtained in Example 468 in tetrahydrofuran (6 ml).After 30 minutes, the mixture thus obtained was warmed up to roomtemperature and stirred overnight. The reaction solution wasconcentrated under reduced pressure, and the resulting residue wasdiluted with chloroform (20 ml) and washed with a 1M-aqueous sodiumhydroxide solution (10 ml). After the aqueous layer was re-extractedwith chloroform (10 ml), the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate). The oil thusobtained was dissolved in methanol (3 ml) at room temperature and4N-hydrochloric acid-dioxane (3 ml) was added thereto. After 1 hour, themixture thus obtained was concentrated under reduced pressure, and theresulting residue was dissolved in methanol (5 ml) and the resultingsolution was adjusted to pH 10 by dropwise addition of a 2M-aqueoussodium hydroxide solution. The solution adjusted was concentrated underreduced pressure and the resulting residue was re-dissolved in methanol(5 ml). Silica gel (1 g) was added thereto and the resulting mixture wasconcentrated under reduced pressure and then dried. The resulting solidwas purified by a silica gel column chromatography (eluent:chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain5-(azepin-4-yloxy)-4-chloro-1H-indazole (128.1 mg, 54%).

IR (neat) cm⁻¹; 3081, 2923, 1497, 1184, 729.

The following compound of Example 595 was synthesized by carrying outreaction according to the method described in Example 594, except forusing tert-butyl 3-hydroxypiperidine-1-carboxylate as a startingmaterial.

EXAMPLE 595 5-(Piperidin-3-yloxy)-4-chloro-1H-indazole

¹H-NMR (DMSO-d₆) δ; 1.60 (1H, m), 1.73 (1H, m), 1.92 (2H, m), 2.93 (2H,m), 3.06 (1H, m), 3.24 (1H, m), 4.40 (1H, m), 7.36 (1H, d, J=9.0 Hz),7.49 (1H, d, J=9.0 Hz), 8.05 (1H, s), 13.37 (1H, s)

EXAMPLE 596 Synthesis of 5-(piperidin-4-yloxy)-4-chloro-1H-indazolehydrochloride

Under a nitrogen atmosphere, triphenylphosphine (280 mg, 1.07 mmol),tert-butyl 4-hydroxypiperidine-1-carboxylate (179 mg, 0.890 mmol) anddiisopropyl azodicarboxylate (193 μl, 0.979 mmol) were added at 0° C. toa solution of the 4-chloro-1H-indazol-5-ol (150 mg, 0.890 mmol) obtainedin Example 468 in tetrahydrofuran (6 ml). After 30 minutes, the mixturethus obtained was heated to room temperature and stirred overnight. Thereaction solution was concentrated under reduced pressure, and theresulting residue was diluted with chloroform and then washed with a1M-aqueous sodium hydroxide solution. After the aqueous layer wasre-extracted with chloroform, the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate). The oil thusobtained was dissolved in methanol (3 ml) at room temperature and4N-hydrochloric acid-dioxane (3 ml) was added thereto. After 1 hour, themixture thus obtained was concentrated under reduced pressure and theresulting residue was washed with ethyl acetate by repulping to obtain5-(piperidin-4-yloxy)-4-chloro-1H-indazole hydrochloride (219.7 mg,86%).

¹H-NMR (DMSO-d₆) δ; 1.93 (2H, m), 2.05 (2H, m), 3.06 (2H, m), 3.24 (2H,m), 4.61 (1H, m), 7.36 (1H, d, J=9.0 Hz), 7.49 (1H, dd, J=9.0, 1.0 Hz),8.03 (1H, d, J=1.0 Hz), 8.99 (2H, brs.).

The following compound of Example 597 was synthesized by carrying outreaction according to the method described in Example 589, except forusing the 4-methoxy-1H-indazol-5-ol obtained in Example 469, as astarting material.

EXAMPLE 597 5-(Azepan-3-yloxy)-4-methoxy-1H-indazole

IR (neat) cm⁻¹; 3174, 2929, 1510, 1230, 928, 723.

EXAMPLE 598 Synthesis of 4-bromo-1H-indazol-5-ol

N-bromosuccinimide (1.06 g, 5.96 mmol) was added to a solution of the1H-indazol-5-ol (800 mg, 5.96 mmol) obtained in Reference Example 4 intetrahydrofuran (20 ml) at room temperature. The resulting mixture wasstirred for 14 hours while being maintained at room temperature. Themixture was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate) to obtain 4-bromo-1H-indazol-5-ol (1.15 g, 91%).

¹H-NMR (DMSO-d₆) δ; 7.37 (1H, d, J=0.92 Hz), 7.40 (1H, d, J=0.92 Hz),7.82 (1H, s), 9.77 (1H, brs), 13.12 (1H, brs).

The following compound of Example 599 was synthesized by carrying outreaction according to the method described in Example 407, except forusing the 4-bromo-1H-indazol-5-ol obtained in Example 598, as a startingmaterial.

EXAMPLE 599 5-(Azepan-4-yloxy)-4-bromo-1H-indazole

MS: m/z=310 (M+1)

The following compounds of Examples 600 to Example 603 were synthesizedby carrying out reaction according to the method described in Example470, except for using the 4-bromo-1H-indazol-5-ol obtained in Example598, as a starting material.

EXAMPLE 600 trans-3-[(4-Bromo-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=310 (M+1)

EXAMPLE 601 cis-3-[(4-Bromo-1H-indazol-5-yl)oxy]cyclohexanamine

MS m/z=310 (M+1)

EXAMPLE 602 trans-4-[(4-Bromo-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=310 (M+1)

EXAMPLE 603 cis-4-[(4-Bromo-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=310 (M+1)

EXAMPLE 604 Synthesis of 4-fluoro-1H-indazol-5-ol (a) Synthesis of6-chloro-2-fluoro-3-methyl-4-nitrophenol

A solution of 6-chloro-2-fluoro-3-methylphenol (9.00 g, 56.1 mmol) indichloromethane (100 ml) was added dropwise to a suspension of 85%nitronium•tetrafluoroborate (9.50 g, 60.8 mmol) in dichloromethane (150ml) at 0 to 5° C. under ice-cooling. The resulting mixture was warmed upto room temperature and stirred for 2 hours while maintaining thetemperature. The mixture was poured into ice water and then partitionedand extracted with chloroform, and the organic layer was washed withwater, dried over anhydrous magnesium sulfate and then filtered. Thefiltrate was concentrated under reduced pressure to obtain a crudeproduct. After the crude product was dissolved in toluene (57 ml) byheating to 80° C., the solution was allowed to cool to 60° C. andmaintained at this temperature. Hexane (171 ml) was added dropwisethereto and the resulting mixture was allowed to cool to roomtemperature and then it was ice-cooled while maintaining temperature.Thereafter, the crystals formed were collected by filtration and driedto obtain 6-chloro-2-fluoro-3-methyl-4-nitrophenol (7.05 g, 61%).

(b) Synthesis of 4-amino-2-fluoro-3-methylphenol

To a solution of 6-chloro-2-fluoro-3-methyl-4-nitrophenol (4.11 g, 19.9mmol) in ethanol (200 ml) were added 10%-palladium/carbon (containing50% water, 410 mg) and ammonium formate (15.1 g, 240 mmol), and theresulting mixture was stirred for 3 hours with heating under refluxwhile maintaining the temperature. The mixture was filtered by the useof Celite and the filtrate was concentrated under reduced pressure toobtain a crude product. The crude product was partitioned by the use ofwater and ethyl acetate (the aqueous layer was adjusted to pH 6 to 7with a 5% aqueous sodium hydrogencarbonate solution and re-extracted),and the organic phase was washed with a 5% aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, and then filtered. Thefiltrate was concentrated under reduced pressure to obtain4-amino-2-fluoro-3-methylphenol (2.89 g, 100%).

(c) Synthesis of 4-(acetylamino)-2-fluoro-3-methylphenyl acetate

Acetic anhydride (4.49 ml, 47.6 mmol) was added dropwise to a solutionof 4-amino-2-fluoro-3-methylphenol (2.80 g, 1.91 mmol) and pyridine(3.53 ml, 43.6 mmol) in ethyl acetate (60 ml) at room temperature, andthe resulting mixture was slowly heated to 65° C. and stirred for 45minutes while being maintained at this temperature. The resultingreaction solution was cooled to room temperature and partitioned by theuse of water and ethyl acetate to find that an insoluble material waspresent. The insoluble material was collected by filtration and dried toobtain 4-(acetylamino)-2-fluoro-3-methylphenyl acetate (679 mg, 15%).The filtrate was concentrated and then extracted with chloroform toobtain a crude product, and the crude product was washed with ethylacetate (8 ml)-hexane (24 ml) by repulping, collected by filtration andthen dried to obtain 4-(acetylamino)-2-fluoro-3-methylphenyl acetate(3.54 g, 79%).

(d) Synthesis of 1-acetyl-4-fluoro-1H-indazol-5-yl acetate

Acetic anhydride (2.83 ml, 30.0 mmol), tetrabutylammonium bromide (161mg, 0.500 mmol), potassium acetate (1.96 g, 20.0 mmol) and isoamylnitrite (1.75 ml, 13.0 mmol) were added in that order to a solution of4-(acetylamino)-2-fluoro-3-methylphenyl acetate (2.25 g, 9.99 mmol) inethyl acetate (30 ml) at room temperature. The resulting mixture wasslowly heated until heating under reflux was caused. Then, the mixturewas stirred for 11 hours while maintaining the temperature. Aftercooling, the mixture was partitioned and extracted with water and ethylacetate, and the organic phase was washed with an aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate and thenfiltered. The filtrate was concentrated under reduced pressure to obtaina crude product. The crude product was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtain1-acetyl-4-fluoro-1H-indazol-5-yl acetate (1.00 g, 38%).

(e) Synthesis of 4-fluoro-1H-indazol-5-ol

A 6N aqueous sodium hydroxide solution (5 ml, 30 mmol) was addeddropwise to a solution of 1-acetyl-4-fluoro-1H-indazol-5-yl acetate (995mg, 3.78 mmol) in methanol (5 ml)-tetrahydrofuran (5 ml) at roomtemperature, and the resulting mixture was stirred for 3.5 hours whilebeing maintained at room temperature. The resulting reaction solutionwas adjusted to pH 5 to 6 by dropwise addition of a 1N aqueoushydrochloric acid solution (about 25 ml) and extracted with ethylacetate, and the organic layer was washed with an aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate and thenfiltered. The filtrate was concentrated under reduced pressure to obtaina crude product. The crude product was purified by a silica gel columnchromatography (eluent: chloroform/ethyl acetate) to obtain4-fluoro-1H-indazol-5-ol (219 mg, 38%).

¹H-NMR (DMSO-d₆) δ; 7.05 (1H, t-like, J=8.4 Hz), 7.18 (1H, d, J=8.8 Hz),7.99 (1H, s), 9.29 (1H, s), 13.07 (1H, brs).

The following compound of Example 605 was synthesized by carrying outreaction according to the method described in Example 407, except forusing the 4-fluoro-1H-indazol-5-ol obtained in Example 604, as astarting material.

EXAMPLE 605 5-(Azepan-4-yloxy)-4-fluoro-1H-indazole

MS: m/z=250 (M+1)

The following compound of Example 606 was synthesized by carrying outreaction according to the method described in Example 470, except forusing the 4-fluoro-1H-indazol-5-ol obtained in Example 604, as astarting material.

EXAMPLE 606 cis-3-[(4-Fluoro-1H-indazol-5-yl)oxy]cyclohexanamine

MS: m/z=250 (M+1)

EXAMPLE 607 Synthesis of 4-(methylthio)-1H-indazol-5-ol (a) Synthesis of4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole

To a solution of the 4-bromo-1H-indazol-5-ol (13.08 g, 61.4 mmol)obtained in Example 598 in dichloromethane (200 ml) were added3,4-dihydro-2H-pyran (16.8 ml, 184 mmol) and p-toluenesulfonic acidpyridine salt (4.64 g, 18.4 mmol), and stirred overnight. The reactionsolution was added to a saturated aqueous sodium hydrogencarbonatesolution and extracted twice with chloroform, and the extract solutionwas dried over anhydrous magnesium sulfate. The solvent was distilledoff and the residue was purified by a silica gel chromatography(hexane/ethyl acetate=10/1 to 5/1) to obtain4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(18.14 g, 77%).

(b) Synthesis of4-(methylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole

Sodium thiomethoxide (0.0265 g, 0.38 mmol) was added to a solution of4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(0.100 g, 0.26 mmol) in N,N-dimethylformamide (1 ml), and the resultingmixture was heated at 70° C. and stirred for 11 hours. The reactionsolution was added to water and extracted three times with toluene/ethylacetate=1/1, and the extract solution was dried over anhydrous magnesiumsulfate. The solvent was distilled off and the residue was purified by asilica gel chromatography (hexane/ethyl acetate=10/1) to obtain4-(methylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(0.0737 g, 80%).

(c) Synthesis of 4-(methylthio)-1H-indazol-5-ol

Trifluoroacetic acid (1 ml) was added to a solution of4-(methylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(0.0730 g, 0.21 mmol) in dichloromethane (1 ml) and stirred for 1 hour.The reaction solution was added to water and extracted three times withethyl acetate and the extract solution was dried over anhydrousmagnesium sulfate. The solvent was distilled off and the residue waspurified by a silica gel chromatography (hexane/ethyl acetate=2/1),crystallized from hexane/ethyl acetate and then dried up to obtain4-(methylthio)-1H-indazol-5-ol (0.0481 g, >99%).

Melting point: 126–128° C.

EXAMPLE 608 Synthesis of 5-(azepan-4-yloxy)-4-(methylthio)-1H-indazolemonohydrochloride (a) Synthesis of tert-butyl4-{[4-(methylthio)-1H-indazol-5-yl]oxy}azepane-1-carboxylate

The tert-butyl 4-hydroxyazepane-1-carboxylate (0.0504 g, 0.23 mmol)obtained in Example 322, (c) and triphenylphosphine (0.0723 g, 0.28mmol) were added to a solution of the 4-(methylthio)-1H-indazol-5-ol(0.0377 g, 0.21 mmol) obtained in Example 607 in tetrahydrofuran (2 ml),and the resulting mixture was ice-cooled. A solution of diisopropylazodicarboxylate (0.0557 g, 0.28 mmol) in tetrahydrofuran (1 ml) wasadded dropwise thereto, and the resulting mixture was slowly heated toroom temperature and stirred overnight. The reaction solution wasconcentrated and then diluted with chloroform, and a 1N-aqueous sodiumhydroxide solution was added thereto, followed by extraction withchloroform (twice). The extract solution was dried over anhydrousmagnesium sulfate. The solvent was distilled off and the residue waspurified by a silica gel chromatography (hexane/ethylacetate=3/1˜2/1˜3/2) to obtain tert-butyl4-{[4-(methylthio)-1H-indazol-5-yl]oxy}azepane-1-carboxylate (0.0318 g,40%).

(b) Synthesis of 5-(azepan-4-yloxy)-4-(methylthio)-1H-indazole

The title compound was synthesized by carrying out reaction according tothe method described in Example 377, except for using tert-butyl4-{[4-(methylthio)-1H-indazol-5-yl]oxy}azepane-1-carboxylate as astarting material.

(c) Synthesis of 5-(azepan-4-yloxy)-4-(methylthio)-1H-indazolemonohydrochloride

The title compound was synthesized by carrying out reaction according tothe method described in Example 327, except for using5-(azepan-4-yloxy)-4-(methylthio)-1H-indazole as a starting material.

IR (neat) cm⁻¹; 2769, 1255, 1245, 1087, 958.

EXAMPLE 609 Synthesis of5-(azepan-4-yloxy)-4-(methylsulfonyl)-1H-indazole monohydrochloride (a)Synthesis of tert-butyl4-{[4-(methylsulfonyl)-1H-indazol-5-yl]oxy}azepane-1-carboxylate

A solution of the tert-butyl4-{[4-(methylthio)-1H-indazol-5-yl]oxy}azepane-1-carboxylate (0.0212 g,0.056 mmol) obtained in Example 608, (a) in chloroform (1 ml) wasice-cooled, and m-chloroperbenzoic acid (0.0221 g, 0.13 mmol) was addedthereto. Then, the resulting mixture was slowly heated to roomtemperature and stirred overnight. The reaction solution was added to asaturated aqueous sodium hydrogencarbonate solution and extracted threetimes with chloroform, and the extract solution was dried over anhydrousmagnesium sulfate. The solvent was distilled off and the residue waspurified by a silica gel chromatography (chloroform/methanol=30/1) toobtain tert-butyl4-{[4-(methylsulfonyl)-1H-indazol-5-yl]oxy}azepane-1-carboxylate (0.0199g, 86%).

(b) Synthesis of 5-(azepan-4-yloxy)-4-(methylsulfonyl)-1H-indazolemonohydrochloride

The title compound was synthesized by carrying out reactions accordingto the methods described in Example 377 and Example 327, except forusing tert-butyl4-{[4-(methylsulfonyl)-1H-indazol-5-yl]oxy}azepane-1-carboxylate as astarting material.

Melting point: 185–187° C.

EXAMPLE 610 Synthesis of2-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The 4-(methylthio)-1H-indazol-5-ol (0.166 g, 0.92 mmol) obtained inExample 607 and thetrans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (0.151 g, 0.61mmol) obtained in Example 323, (a) were added to a solution ofcyanomethylenetri-n-butylphosphorane (0.247 g, 0.92 mmol) in toluene (6ml), and the resulting mixture was heated at 100° C. and stirred for 7hours. The reaction solution was concentrated and then diluted withchloroform, and a 1N-aqueous sodium hydroxide solution was addedthereto, followed by extraction with chloroform (three times). Theextract solution was dried over anhydrous magnesium sulfate. The solventwas distilled off and the residue was purified by a silica gelchromatography (hexane/ethyl acetate=2/1˜1/1) to obtain2-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione(0.144 g: 58%).

Melting point: 211–212° C.

EXAMPLE 611 Synthesis ofcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanaminemonohydrochloride (a) Synthesis ofcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using the2-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 610, as a starting material.

(b) Synthesis ofcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanaminemonohydrochloride

The title compound was synthesized by carrying out reaction according tothe method described in Example 327, except for usingcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine as a startingmaterial.

Melting point: 199–201° C.

EXAMPLE 612 Synthesis ofcis-4-{[4-(methylsulfonyl)-1H-indazol-5-yl]oxy}cyclohexanamine (a)Synthesis of2-(cis-4-{[4-(methylsulfonyl)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneand2-(cis-4-{[4-(methylsulfinyl)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compounds were synthesized by carrying out reaction accordingto the method described in Example 609, (a), except for using the2-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 610, as a starting material.

(b) Synthesis ofcis-4-{[4-(methylsulfonyl)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using2-(cis-4-{[4-(methylsulfonyl)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneas a starting material.

IR (neat) cm⁻¹; 1300, 1228, 1128, 978, 931.

EXAMPLE 613 Synthesis ofcis-4-{[4-(methylsulfinyl)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using the2-(cis-4-{[4-(methylsulfinyl)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 612, (a), as a starting material.

IR (neat) cm⁻¹; 3168, 1284, 1228, 1018, 931.

EXAMPLE 614 Synthesis of2-(cis-3-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 608, (a), except for using thetrans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 385, (b), as a starting material.

Melting point: 156–157° C.

EXAMPLE 615 Synthesis ofcis-3-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using the2-(cis-3-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 614, as a starting material.

Melting point: 140° C.

EXAMPLE 616 Synthesis oftrans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine (a)Synthesis of2-(trans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 610, except for using thecis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 323, (c), as a starting material.

(b) Synthesis oftrans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using2-(trans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneas a starting material.

Melting point: 138–140° C.

EXAMPLE 617 Synthesis of2-(trans-3-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 610, except for using thecis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 326, (d), as a starting material.

IR (neat) cm⁻¹; 3172, 1697, 1232, 1134, 945.

EXAMPLE 618 Synthesis oftrans-3-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using the2-(trans-3-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 617, as a starting material.

Melting point: 112–113° C.

EXAMPLE 619 Synthesis ofcis-N,N-dimethyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 140, except for using thecis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine obtained inExample 611, (a), as a starting material.

Melting point: 157–159° C.

EXAMPLE 620 Synthesis oftrans-N,N-dimethyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 140, except for using thetrans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine obtained inExample 616, as a starting material.

Melting point: 139–140° C.

The following compounds of Example 621 and Example 622 were synthesizedby carrying out reaction according to the method described in Example391, except for using thecis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine obtained inExample 611, (a), as a starting material.

EXAMPLE 621N-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)propanamide

Melting point: 155–156° C.

EXAMPLE 622N-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)benzamide

Melting point: 146–148° C.

EXAMPLE 623 Synthesis ofcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}-N-propylcyclohexanaminemonohydrochloride (a) Synthesis ofcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}-N-propylcyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 399, except for using theN-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)propanamideobtained in Example 621, as a starting material.

(b) Synthesis ofcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}-N-propylcyclohexanaminemonohydrochloride

The title compound was synthesized by carrying out reaction according tothe method described in Example 327, except for usingcis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}-N-propylcyclohexanamine as astarting material.

Melting point: 178–179° C.

EXAMPLE 624 Synthesis ofcis-N-benzyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanaminemonohydrochloride (a) Synthesis ofcis-N-benzyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 399, except for using theN-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)benzamideobtained in Example 622, as a starting material.

(b) Synthesis ofcis-N-benzyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanaminemonohydrochloride

The title compound was synthesized by carrying out reaction according tothe method described in Example 327, except for usingcis-N-benzyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine as astarting material.

Melting point: 232° C. (decomp.)

EXAMPLE 625 Synthesis ofN-(trans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)propanamide

The title compound was synthesized by carrying out reaction according tothe method described in Example 391, except for using thetrans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine obtained inExample 616, as a starting material.

Melting point: 201–202° C.

EXAMPLE 626 Synthesis oftrans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}-N-propylcyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 399, except for using theN-(trans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)propanamideobtained in Example 625, as a starting material.

Melting point: 168–169° C.

EXAMPLE 627 Synthesis oftrans-N-benzyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine(a) Synthesis ofN-(trans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)benzamide

The title compound was synthesized by carrying out reaction according tothe method described in Example 391, except for using thetrans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine obtained inExample 616, as a starting material.

(b) Synthesis oftrans-N-benzyl-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 399, except for usingN-(trans-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)benzamide asa starting material.

Melting point: 135.5–136° C.

EXAMPLE 628 Synthesis of 4-(ethylthio)-1H-indazol-5-ol (a) Synthesis of4-(ethylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole

The title compound was synthesized by carrying out reaction according tothe method described in Example 607, (b), except for using sodiumthioethoxide as a starting material.

(b) Synthesis of 4-(ethylthio)-1H-indazol-5-ol

The title compound was synthesized by carrying out reaction according tothe method described in Example 607, (c), except for using4-(ethylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazoleas a starting material.

Melting point: 116° C.

EXAMPLE 629 Synthesis of2-(cis-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 610, except for using the4-(ethylthio)-1H-indazol-5-ol obtained in Example 628, as a startingmaterial.

¹H-NMR (CDCl₃) δ; 1.26 (3H, t, J=7.3 Hz), 1.73–1.61 (2H, m), 2.29–2.21(2H, m), 2.98–2.86 (2H, m), 3.18 (2H, q, J=7.3 Hz), 4.28–4.18 (1H, m),4.67–4.63 (1H, m), 7.19 (1H, d, J=9.0 Hz), 7.38 (1H, d, J=9.0 Hz),7.74–7.68 (2H, m), 7.87–7.81 (2H, m), 8.23 (1H, s).

EXAMPLE 630 Synthesis ofcis-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanaminemonohydrochloride (a) Synthesis ofcis-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using the2-(cis-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 629, as a starting material.

(b) Synthesis ofcis-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanaminemonohydrochloride

The title compound was synthesized by carrying out reaction according tothe method described in Example 327, except for usingcis-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine as a startingmaterial.

Melting point: 190° C. (decomp.)

EXAMPLE 631 Synthesis ofcis-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine (a) Synthesisof2-(cis-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 610, except for using thetrans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 385, (b) and the 4-(ethylthio)-1H-indazol-5-ol obtained inExample 628, as starting materials.

(b) Synthesis ofcis-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using2-(cis-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneas a starting material.

Melting point: 109.5–110.5° C.

EXAMPLE 632 Synthesis oftrans-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine (a)Synthesis of2-(trans-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 610, except for using thecis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 323, (c) and the 4-(ethylthio)-1H-indazol-5-ol obtained inExample 628, as starting materials.

(b) Synthesis oftrans-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using2-(trans-4-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneas a starting material.

Melting point: 157–158° C.

EXAMPLE 633 Synthesis oftrans-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine (a)Synthesis of2-(trans-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione

The title compound was synthesized by carrying out reaction according tothe method described in Example 610, except for using thecis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 326, (d) and the 4-(ethylthio)-1H-indazol-5-ol obtained inExample 628, as starting materials.

(b) Synthesis oftrans-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 381, except for using2-(trans-3-{[4-(ethylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dioneas a starting material.

Melting point: 111–112° C.

EXAMPLE 634 Synthesis of 4-propoxy-1H-indazol-5-ol (a) Synthesis of1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-ol

Under a nitrogen atmosphere, a 1.57M-n-butyllithium/hexane solution(12.00 ml, 0.0189 mol) was added dropwise to a solution of the4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(6.0 g, 0.0157 mol) obtained in Example 607 in tetrahydrofuran (120 ml)at −78° C. over a period of 15 minutes. After 30 minutes, a solution oftrimethoxyborane (2.65 ml, 0.0236 mol) in tetrahydrofuran (30 ml) wasadded dropwise thereto over a period of 5 minutes and the resultingmixture was slowly heated. After 15 hours, acetic acid (1.98 ml, 0.0346mol) was added thereto. After 15 minutes, a solution of 30%-aqueoushydrogen peroxide solution (4.46 ml, 0.0393 mol) in tetrahydrofuran (20ml) was added dropwise thereto over a period of 10 minutes, and theresulting mixture was slowly heated to room temperature. After 8.5hours, a 30%-aqueous hydrogen peroxide solution (4.72 mmol) was furtheradded thereto. After 15 hours, a 10%-aqueous sodium hydrogensulfitesolution and a saturated aqueous sodium hydrogencarbonate solution wereadded thereto, and the resulting mixture was poured into water andextracted with ethyl acetate. The extract solution was concentratedunder reduced pressure and the resulting residue was purified by asilica gel column chromatography (eluent: hexane/ethyl acetate). Theresidue purified was concentrated under reduced pressure and theresulting residue was washed with hexane by repulping to obtain1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-ol(2.9892 g, 42%).

(b) Synthesis of4-propoxy-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole

Under a nitrogen atmosphere, n-propyl iodide (257 μl, 2.64 mmol) andcesium carbonate (860 mg, 2.64 mmol) were added to a solution of1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-ol(700 mg, 2.20 mmol) in N,N-dimethylformamide (7 ml) at room temperature.After 2 hours, the reaction solution was poured into water and extractedwith ethyl acetate. The extract solution was concentrated under reducedpressure and the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtain4-propoxy-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(852.6 mg).

(c) Synthesis of 4-propoxy-1H-indazol-5-ol

Under a nitrogen atmosphere, trifluoroacetic acid (5.5 ml) was added toa solution of4-propoxy-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(852.6 mg) in dichloromethane (16.5 ml) at room temperature. After 2.5hours, the reaction solution was poured onto ice, adjusted to pH 7 withan aqueous sodium hydroxide solution, and then extracted with ethylacetate. The extract solution was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate). The residue purified wasconcentrated under reduced pressure and the resulting residue was washedwith diethyl ether/hexane by repulping to obtain4-propoxy-1H-indazol-5-ol (338.2 g, 80%, two steps).

IR (neat) cm⁻¹; 3282, 2931, 1305, 1081, 800.

EXAMPLE 635 Synthesis of 4-nitro-1H-indazol-5-ol

Under a nitrogen atmosphere, a solution of tetrafluoroborate nitrite(110 mg, 0.783 mmol) in acetonitrile (3 ml) was added dropwise to asuspension of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained inReference Example 4 in acetonitrile (4.0 ml) at −35° C. over a period of10 minutes, and the resulting mixture was slowly heated to 0° C. After 2hours, the reaction solution was poured into water and extracted withethyl acetate. The extract solution was concentrated under reducedpressure and the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate). The residue purified wasconcentrated under reduced pressure and the resulting residue was washedwith ethanol/diisopropyl ether by repulping to obtain4-nitro-1H-indazol-5-ol (59.8 mg, 45%).

IR (neat) cm⁻¹; 3091, 1629, 1500, 1147, 933, 702.

EXAMPLE 636 Synthesis ofcis-3-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride (a)cis-3-[(4-Propoxy-1H-indazol-5-yl)oxy]cyclohexanamine

Under a nitrogen atmosphere, triphenylphosphine (164 mg, 0.624 mmol),the trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (128 mg,0.520 mmol) obtained in Example 385, (b) and diisopropylazodicarboxylate (113 μl, 0.572 mmol) were added at 0° C. to a solutionof the 4-propoxy-1H-indazol-5-ol (100 mg, 0.520 mmol) obtained inExample 634 in tetrahydrofuran (4 ml). After 30 minutes, the resultingmixture was heated to room temperature and stirred overnight. Thereaction solution was concentrated under reduced pressure, and theresulting residue was diluted with chloroform and washed with a1M-aqueous sodium hydroxide solution. The aqueous layer was re-extractedwith chloroform and then the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate). To the oil thusobtained was added a 30%-methylamine-ethanol solution at roomtemperature, and the resulting mixture was refluxed. After 2 hours, themixture was concentrated under reduced pressure at room temperature, andthe resulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia))to obtain cis-3-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanamine (82.3mg, 55%).

(b) Synthesis of cis-3-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanaminehydrochloride

Under a nitrogen atmosphere, 1M-hydrochloric acid-diethyl ether (341 μl,0.341 mmol) was added dropwise to a solution ofcis-3-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanamine (82.3 mg, 0.284mmol) in methanol (2 ml) at room temperature. After 1 hour, the mixturethus obtained was concentrated under reduced pressure and the resultingresidue was crystallized from ethyl acetate, followed by filtrationunder reduced pressure, and then drying. The solid thus obtained waswashed with hexane by repulping to obtaincis-3-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride(76.8 mg, 83%).

IR (neat) cm⁻¹; 2939, 1508, 1228, 1147, 939.

The following compound of Example 637 was synthesized by carrying outreaction according to the method described in Example 636, except forusing the trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 323, (a), as a starting material.

EXAMPLE 637 Synthesis ofcis-4-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride

¹H-NMR (DMSO-d₆) δ; 1.01 (3H, t, J=7.4 Hz), 1.60 (2H, m), 1.70–1.86 (6H,m), 1.91 (2H, m), 3.08 (1H, brs), 4.24 (2H, t, J=6.5 Hz), 4.29 (1H, m),7.09 (2H, s), 7.90 (3H, brs), 8.09 (1H, s), 13.00 (1H, brs).

The following compound of Example 638 was synthesized by carrying outreaction according to the method described in Example 634.

EXAMPLE 638 4-Isopropoxy-1H-indazol-5-ol

¹H-NMR (DMSO-d₆) δ; 1.25 (6H, d, J=6.2 Hz), 4.63 (1H, qq, J=6.2, 6.2Hz), 6.97 (1H, d, J=8.8 Hz), 7.01 (1H, d, J=8.8 Hz), 7.89 (1H, s), 8.49(1H, s), 12.78 (1H, brs).

EXAMPLE 639 Synthesis ofcis-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methanesulfonamide

Under a nitrogen atmosphere, triethylamine (49.5 μl, 0.355 mmol) wasadded at 0° C. to a solution of thecis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride (100mg, 0.355 mmol) obtained in Example 410 in tetrahydrofuran (4 ml),followed by adding dropwise thereto a solution of methanesulfonylchloride (28 μl, 0.362 mmol) in dichloromethane (2 ml). After 30minutes, the resulting mixture was heated to room temperature andtriethylamine (0.355 mmol) was further added thereto. After 2 hours,triethylamine (0.355 mmol) and methanesulfonyl chloride (0.355 mmol)were further added thereto. After 2 hours, the reaction solution waspoured into water and extracted with ethyl acetate. The extract solutionwas concentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: chloroform/ethylacetate) to obtaincis-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methanesulfonamide(31.7 mg, 28%).

IR (neat) cm⁻¹; 3249, 2933, 1508, 1298, 1155, 945.

EXAMPLE 640 Synthesis ofcis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride(a) Synthesis ofcis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine

Under a nitrogen atmosphere, the 4-isopropoxy-1H-indazol-5-ol (118 mg,0.614 mmol) obtained in Example 638 and thetrans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (100 mg, 0.408mmol) obtained in Example 385, (b) were added to a solution of90%-cyanomethylenetri-n-butylphosphorane (155 mg, 0.614 mmol) in toluene(4 ml) at room temperature, and the resulting mixture was heated to 100°C. After 4.5 hours, the reaction solution was concentrated under reducedpressure and the resulting residue was diluted with chloroform andwashed with a 1M-aqueous sodium hydroxide solution. The aqueous layerwas re-extracted with chloroform and then the organic layer was driedover anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate). To the resulting oil was added a 30%-methylamine-ethanolsolution at room temperature, and the resulting mixture was refluxed.After 4 hours, the mixture was concentrated under reduced pressure atroom temperature, and the resulting residue was purified by a silica gelcolumn chromatography (eluent: chloroform/methanol→chloroform/methanol(1%-aqueous ammonia)) to obtaincis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine (71.0 mg, 60%).

(b) Synthesis ofcis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride

Under a nitrogen atmosphere, 1M-hydrochloric acid-diethyl ether (350 μl,0.341 mmol) was added dropwise to a solution ofcis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine (84.3 mg, 0.284mmol) in isopropanol (2 ml) at room temperature. After 1 hour, themixture thus obtained was concentrated under reduced pressure and theresulting residue was crystallized from ethyl acetate, followed byfiltration under reduced pressure, and then drying. The solid thusobtained was washed with hexane by repulping to obtaincis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride(70.1 mg, 74%).

IR (neat) cm⁻¹; 2937, 1508, 1227, 1087, 928.

The following compound of Example 641 was synthesized by carrying outreaction according to the method described in Example 640, except forusing the trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dioneobtained in Example 323, (a), as a starting material.

EXAMPLE 641 cis-4-[(4-Isopropoxy-1H-indazol-5-yl)oxy]cyclohexanaminehydrochloride

IR (neat) cm⁻¹; 2935, 1506, 1228, 1083, 939.

EXAMPLE 642 Synthesis ofcis-4-methyl-5-[(4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole andcis-4({4-methyl-1H-indazol-5-yl}oxy)cyclohexyl}amino)butan-1-ol (a)Synthesis ofcis-1-{4-[(1-acetyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}pyrrolidine-2,5-dione

Under a nitrogen atmosphere, succinic anhydride (105 mg, 1.05 mmol) andtriethylamine (279 μl, 2.00 mmol) were added to a solution of thecis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride (282mg, 1.00 mmol) obtained in Example 410 in toluene (6 ml) at roomtemperature, and the resulting mixture was refluxed. After 5.5 hours,the reaction solution was poured into water and extracted with ethylacetate. The extract solution was concentrated under reduced pressure,and to a solution of the resulting residue in ethyl acetate (4 ml) wasadded acetyl chloride (214 μl, 3.00 mmol), and the resulting mixture washeated to 100° C. Dimethylformamide (2 ml) was added thereto because asolid was precipitated. After 2 hours, the reaction solution was pouredinto water and extracted with ethyl acetate. The extract solution wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtaincis-1-{4-[(1-acetyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}pyrrolidine-2,5-dione(123.7 mg, 33%).

(b) Synthesis ofcis-4-methyl-5-[(4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole andcis-4({4-methyl-1H-indazol-5-yl}oxy)cyclohexyl}amino)butan-1-ol

Under a nitrogen atmosphere, 28%-sodium methoxide (64 μl, 0.311 mmol)was added at 0° C. to a suspension ofcis-1-{4-[(1-acetyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}pyrrolidine-2,5-dione(500 mg, 0.311 mmol) in a mixture of methanol (3 ml) and tetrahydrofuran(3 ml). After 10 minutes, a saturated aqueous ammonium chloride solutionwas added to the reaction solution and the resulting mixture was pouredinto water and extracted with ethyl acetate. The extract solution wasconcentrated under reduced pressure, and to a solution of the resultingresidue in tetrahydrofuran (4 ml) was added lithium aluminum hydride (47mg, 1.25 mmol) and the resulting mixture was refluxed. After 4 hours,water, a 2M-aqueous sodium hydroxide solution and water were addedthereto in that order, and the resulting mixture was filtered by the useof Celite. The filtrate was concentrated under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia))to obtain cis-4-methyl-5-[(4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole(59.6 mg, 64%) andcis-4({4-methyl-1H-indazol-5-yl}oxy)cyclohexyl}amino)butan-1-ol (15.4mg, 16%).

IR (neat) cm⁻¹; 3156, 2943, 1514, 1222, 1095, 951.

EXAMPLE 643 Synthesis of 4-morpholin-4-yl-1H-indazol-5-ol (a) Synthesisof4-morpholine-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole

Under a nitrogen atmosphere, morpholine (1.10 ml, 0.0126 mol),(oxydi-2,1-phenylene)bis(diphenylphosphine) (226 mg, 0.420 mmol), sodiumt-butoxide (1.41 g, 0.0147 mol) andtris(dibenzylideneacetone)dipalladium(0)-chloroform (217 mg, 0.210 mmol)were added to a solution of the4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(395 mg, 0.0105 mol) obtained in Example 607 in dioxane (80 ml) at roomtemperature, and the resulting mixture was refluxed. After 2 hours, thereaction solution was concentrated under reduced pressure and theresulting residue was poured into water and extracted with ethylacetate. The extract solution was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (hexane/ethyl acetate) to obtain4-morpholine-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(2.4267 g, 61%).

(b) Synthesis of 4-morpholin-4-yl-1H-indazol-5-ol

Under a nitrogen atmosphere, trifluoroacetic acid (12.5 ml) was added toa solution of4-morpholine-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(2.4267 g, 6.43 mol) in dichloromethane (50 ml) at room temperature.After 3 hours, the reaction solution was poured onto ice and adjusted topH 6 with an aqueous sodium hydroxide solution to separate adichloromethane layer, and then the aqueous layer was extracted withethyl acetate. The extract solution was concentrated under reducedpressure and the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate). The residue purified wasconcentrated under reduced pressure and the resulting residue was washedwith diethyl ether/hexane by repulping to obtain4-morpholin-4-yl-1H-indazol-5-ol (882.4 mg, 63%).

¹H-NMR (DMSO-d₆) δ; 3.15 (4H, m), 3.77 (4H, m), 6.95 (1H, d, J=8.8 Hz),7.08 (1H, d, J=8.8 Hz), 8.06 (1H, s), 8.24 (1H, s), 12.79 (1H, s).

The following compounds of Examples 644 and 645 were synthesized bycarrying out reaction according to the method described in Example 640,(a), except for using the 4-morpholin-4-yl-1H-indazol-5-ol obtained inExample 643, as a starting material.

EXAMPLE 644 cis-4-[(4-morpholine-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 2941, 1495, 1219, 1113, 937.

EXAMPLE 645 Synthesis ofcis-3-[(4-morpholine-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 2931, 1506, 1220, 1111, 930.

EXAMPLE 646 Synthesis of{cis-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine (a)Synthesis oftrans-2-[(2-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione

Under a nitrogen atmosphere, a solution of trans-2-cyanohexanol (1.0 g,7.99 mmol) in tetrahydrofuran (10 ml) was added dropwise to a solutionof lithium aluminum hydride (1.21 g, 0.0320 mol) in tetrahydrofuran (15ml) at 0° C., and the resulting mixture was refluxed. After 2 hours,water, a 2M-aqueous sodium hydroxide solution and water were added inthat order to the reaction solution, and the resulting mixture wasfiltered by the use of Celite. To the filtrate was added 1M-hydrochloricacid-diethyl ether (9.59 ml, 9.59 mmol), and the resulting mixture wasconcentrated under reduced pressure. Potassium carbonate (1.99 g, 0.0144mol) and ethoxycarbonylphthalimide (1.93 g, 8.79 mmol) were added to anaqueous solution (30 ml) of the concentration residue at roomtemperature. After 15 hours, the reaction solution was poured into waterand extracted with ethyl acetate, and the organic layer was dried overanhydrous magnesium sulfate. The organic layer dried was concentratedunder reduced pressure and the resulting residue was purified by asilica gel column chromatography (eluent: hexane/ethyl acetate) toobtain trans-2-[(2-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione(1.1736 g, 57%).

(b) Synthesis of{cis-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine

Reaction was carried out according to the method described in Example640, (a), except for using the 4-methyl-1H-indazol-5-ol obtained inExample 402, as a staring material.

¹H-NMR (DMSO-d₆) δ; 1.24–1.85 (11H, m), 2.40 (3H, s), 2.69 (2H, m), 2.03(1H, m), 2.27 (1H, m), 2.70 (2H, m), 4.59 (1H, m), 7.21 (1H, d, J=9.0Hz), 7.25 (1H, d, J=9.0 Hz), 7.98 (1H, s), 12.81 (1H, s).

EXAMPLE 647 Synthesis oftrans-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (a) Synthesis ofcis-2-(2-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione

Under a nitrogen atmosphere, a solution of monomethyl phthalate (1.31 g,7.31 mmol) and N,N-diisopropylamine (1.72 ml, 7.31 mmol) intetrahydrofuran (10 ml) was added dropwise to a solution ofbenzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate(3.77 g, 7.31 mmol) in tetrahydrofuran (10 ml) over a period of 15minutes at room temperature. After 40 minutes, the solution thusprepared was slowly dropped into a solution of cis-2-aminocyclohexanolhydrochloride (1.0 g, 6.65 mmol) and triethylamine (1.01 ml, 7.31 mmol)in tetrahydrofuran (10 ml). After 3 hours, p-toluenesulfonic acid (35mg) was added thereto, and the resulting mixture was refluxed. After 5hours, water was added thereto and the resulting mixture was poured intoa saturated aqueous sodium hydroxide solution and extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate.The organic layer dried was concentrated under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate) and purified again by a silica gel columnchromatography (eluent: chloroform/ethyl acetate) to obtaincis-2-(2-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.5746 g, 97%).

(b) Synthesis of trans-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Reaction was carried out according to the method described in Example640, (a), except for using the 4-methyl-1H-indazol-5-ol obtained inExample 402, as a staring material.

IR (neat) cm⁻¹; 3161, 1508, 1219, 1092, 941.

EXAMPLE 648 Synthesis of{trans-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylaminehydrochloride (a) Synthesis ofcis-2-[(2-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione

Under a nitrogen atmosphere, potassium carbonate (375 mg, 2.72 mmol) andethoxycarbonylphthalimide (364 mg, 1.66 mmol) were added to an aqueoussolution (4 ml) of 2-aminomethylcyclohexanol hydrochloride (250 mg, 1.51mmol) at room temperature. After 3 hours, the reaction solution waspoured into water and extracted with ethyl acetate, and the organiclayer was dried over anhydrous magnesium sulfate. The organic layerdried was concentrated under reduced pressure and the resulting residuewas purified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtaincis-2-[(2-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (291.6mg, 75%).

(b) Synthesis of{trans-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine

Reaction was carried out according to the method described in Example640, (a), except for using the 4-methyl-1H-indazol-5-ol obtained inExample 402, as a staring material.

(c) Synthesis of{trans-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylaminehydrochloride

Under a nitrogen atmosphere, 1M-hydrochloric acid-diethyl ether (249 μl,0.249 mmol) was added to a solution of{trans-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine (53.8 mg,0.207 mmol) in 2-propanol (1 ml) at room temperature. After 1 hour, thereaction solution was concentrated under reduced pressure and theresulting residue was crystallized from 2-propanol/acetonitrile toobtain {trans-2-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylaminehydrochloride (49.4 mg, 81%).

IR (neat) cm⁻¹; 2929, 1508, 1259, 1080, 810.

EXAMPLE 649 Synthesis of{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine (a)Synthesis of 1-cyanocyclohexan-3-one

Under a nitrogen atmosphere, ammonium chloride (4.17 g, 0.078 mol) andpotassium cyanide (6.77 g, 0.104 mol) were added to a solution of2-cyclohexen-1-one (5.0 g, 0.052 mol) in a 15%-aqueousN,N-dimethylformamide solution (60 ml) at room temperature, and theresulting mixture was heated to 100° C. After 3 hours, the reactionsolution was poured into water and extracted with chloroform, and theorganic layer was dried over anhydrous magnesium sulfate. The organiclayer dried was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate) to obtain 1-cyanocyclohexan-3-one (345.4 mg,5.4%).

(b) Synthesis ofcis-2-[(3-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione

Under a nitrogen atmosphere, lithium aluminum hydride (92 mg, 2.44 mmol)was added to a solution of 1-cyanocyclohexan-3-one (100 mg, 0.812 mmol)in tetrahydrofuran (2 ml) at room temperature, and the resulting mixturewas refluxed. After 5 hours, water, an aqueous sodium hydroxide solutionand water were added in that order to the reaction solution, and theresulting mixture was filtered under reduced pressure. Thereafter,1M-hydrochloric acid-diethyl ether (974 μl, 0.974 mmol) was added to thefiltrate. The resulting mixture was concentrated under reduced pressure,and to an aqueous solution (4 ml) of the resulting residue were addedpotassium carbonate (202 mg, 1.46 mmol), ethoxycarbonylphthalimide (196mg, 0.893 mmol) and acetonitrile (1 ml) at room temperature. After 21hours, the reaction solution was poured into water and extracted withethyl acetate, and the organic layer was dried over anhydrous magnesiumsulfate. The organic layer dried was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) and purified again by asilica gel column chromatography (eluent: chloroform/ethyl acetate) toobtain cis-2-[(3-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione(83.5 mg, 40%, cis:trans=12:1).

(c) Synthesis of{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine

Reaction was carried out according to the method described in Example640, (a), except for using the 4-methyl-1H-indazol-5-ol obtained inExample 402, as a staring material.

¹H-NMR (CDCl₃) δ; 1.04 (1H, m), 1.26 (1H, m), 1.47 (1H, m), 1.59 (1H,m), 1.74–2.10 (5H, m), 2.51 (3H, s), 2.55 (2H, m), 4.54 (1H, m), 7.11(1H, d, J=9.0 Hz), 7.23 (1H, d, J=9.0 Hz), 8.02 (1H, s).

EXAMPLE 650 Synthesis of{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylaminehydrochloride (a) Synthesis of cis-3-methoxycyclohexanecarboamide andtrans-3-methoxycyclohexanecarboamide

Under a nitrogen atmosphere, thionyl chloride (902 mg, 7.59 mmol) wasadded to a solution of 3-methoxycyclohexylcarboxylic acid (1.0 g, 6.32mmol, cis:trans=4:3) in toluene (20 ml) at room temperature, and theresulting mixture was heated to 50° C. After 2 hours,N,N-dimethylformamide (4 drops) was added thereto because no reactionhad took place. After 1 hour, the mixture thus obtained was concentratedunder reduced pressure, and a solution of the resulting residue inchloroform (20 ml) was added dropwise to a saturated ammonia-chloroformsolution (15 ml) at room temperature. After 19 hours, the reactionsolution was filtered under reduced pressure and the filtrate wasconcentrated under reduced pressure. Then, the resulting residue waspurified by a silica gel column chromatography (eluent:chloroform/methanol) to obtain cis-3-methoxycyclohexanecarboamide (364.1mg, 37%) and trans-3-methoxycyclohexanecarboamide (261.3 mg, 26%).

(b) Synthesis oftrans-2-[(3-methoxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione

Reaction was carried out according to the method described in Example649, (b).

(c) Synthesis oftrans-2-[(3-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione

Under a nitrogen atmosphere, a solution of sodium iodide (247 mg, 1.65mmol) and 15-crown-5 (327 μl, 1.65 mmol) in dichloromethane (2.7 ml) wasslowly dropped into a solution oftrans-2-[(3-methoxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (100mg, 0.366 mmol) in dichloromethane (2 ml) at −40° C. After 10 minutes, a1M-tribromoborane-dichloromethane solution (1.10 ml, 1.10 mmol) wasadded dropwise thereto. After 1 hour, the mixture thus obtained wasslowly heated to be adjusted to 0° C. 2.5 hours after the start of theheating. After standing at room temperature for 14 hours, the reactionsolution was poured onto ice and extracted with chloroform. The extractsolution was concentrated under reduced pressure and the resultingresidue was purified by a silica gel column chromatography (eluent:hexane/ethyl acetate) to obtaintrans-2-[(3-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (63.2mg, 67%).

(d) Synthesis of{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine

Reaction was carried out according to the method described in Example640, (a), except for using the 4-methyl-1H-indazol-5-ol obtained inExample 402, as a starting material.

(e) Synthesis of{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylaminehydrochloride

Under a nitrogen atmosphere, 1M-hydrochloric acid-diethyl ether (119 μl,0.119 mmol) was added to a solution of{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine (25.8 mg,0.0995 mmol) in 2-propanol (1 ml) at room temperature. After 1 hour, thereaction solution was concentrated under reduced pressure and theresulting residue was crystallized from 2-propanol/diethyl ether toobtain {cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylaminehydrochloride (21.8 mg, 74%).

¹H-NMR (DMSO-d₆) δ; 0.93 (1H, m), 1.11 (1H, m), 1.28 (2H, m), 1.67–1.78(3H, m), 2.02 (1H, m), 2.11 (1H, m), 2.37 (3H, s), 2.69 (2H, m), 4.03(1H, m), 7.14 (1H, d, J=9.0 Hz), 7.26 (1H, d, J=9.0 Hz), 7.86 (3H,brs.), 8.01 (1H, s)

EXAMPLE 651 Synthesis oftrans-N-{4-[(1-acetyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine

Under a nitrogen atmosphere, triethylamine (112 μl, 0.807 mmol) andacetyl chloride (25.2 μl, 0.355 mmol) were added to a solution ofmonohydrochloride (100 mg, 0.323 mmol) of thetrans-N,N-dimethyl-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amineobtained in Example 412 in N,N-dimethylformamide (2 ml) at roomtemperature. After 1 hour, triethylamine (0.420 mmol) and acetylchloride (0.355 mmol) were further added thereto. After 2 hours, thereaction solution was poured into water and extracted with chloroform,and the organic layer was dried over anhydrous magnesium sulfate. Theorganic layer dried was concentrated under reduced pressure and theresulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol) to obtaintrans-N-{4-[(1-acetyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine(20.1 mg, 20%).

IR (neat) cm⁻¹; 2937, 1705, 1508, 1252, 935, 814.

EXAMPLE 652 Synthesis of Methyltrans-5-{[4-(dimethylamino)cyclohexyl]oxy}-4-methyl-1H-indazole-1-carboxylate

Under a nitrogen atmosphere, triethylamine (135 μl, 0.968 mmol) andmethyl chloroformate (37 μl, 0.484 mmol) were added at 0° C. to asolution of monohydrochloride (100 mg, 0.323 mmol) of thetrans-N,N-dimethyl-N-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amineobtained in Example 412 in acetone (2 ml). After 15 minutes, the mixturethus obtained was warmed up to room temperature. After 1 hour,triethylamine (0.646 mmol) and methyl chloroformate (0.484 mmol) werefurther added thereto. After 1 hour, chloroform (2 ml) was addedthereto. After another 3 hours, the reaction solution was poured into asaturated aqueous sodium chloride solution and extracted withchloroform, and the organic layer was dried over anhydrous magnesiumsulfate. The organic layer dried was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol) to obtain methyltrans-5-{[4-(dimethylamino)cyclohexyl]oxy}-4-methyl-1H-indazole-1-carboxylate(38.7 mg, 36%).

¹H-NMR (DMSO-d₆) δ; 1.22–1.47 (4H, m), 1.84 (2H, m), 2.05 (2H, m), 2.21(6H, s), 2.26 (1H, m), 2.39 (3H, s), 4.00 (3H, s), 4.17 (1H, m), 7.38(1H, d, J=9.0 Hz), 7.85 (1H, d, J=9.0 Hz), 8.48 (1H, s).

EXAMPLE 653 Synthesis of{cis-1-methyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine(a) Synthesis of methyl cis-3-methoxycyclohexanecarboxylate and methyltrans-3-methoxycyclohexanecarboxylate

Under a nitrogen atmosphere, thionyl chloride (11.3 g, 0.0948 mol) wasslowly dropped into methanol (30 ml) at −5° C. over a period of 20minutes. After 15 minutes, a solution of 3-methoxycyclohexylcarboxylicacid (5.0 g, 0.0316 mol, cis:trans=4:3) in methanol (30 ml) was addeddropwise thereto over a period of 15 minutes. After 2.5 hours, thereaction solution was concentrated under reduced pressure, and theresulting residue was diluted with ethyl acetate and washed with asaturated aqueous sodium hydrogencarbonate solution. The aqueous layerwas re-extracted with ethyl acetate and then the organic layer was driedover anhydrous magnesium sulfate. The organic layer dried wasconcentrated under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain methyl cis-3-methoxycyclohexane-carboxylate (3.0673g, 56%) and methyl trans-3-methoxycyclohexanecarboxylate (1.5859 g,29%).

(b) Synthesis of methyl 3-methoxy-1-methylcyclohexanecarboxylate

Under a nitrogen atmosphere, a 2M-lithium diisopropylamide solution(7.32 ml, 0.0146 mmol) was added dropwise to a solution of methylcis-3-methoxycyclohexane-carboxylate (1.80 g, 0.0105 mol) intetrahydrofuran (36 ml) at −78° C. over a period of 15 minutes. After 3hours, a solution of methyl iodide (4.45 g, 0.0314 mmol) intetrahydrofuran (9 ml) was added dropwise thereto over a period of 20minutes, and the resulting mixture was slowly warmed up to 0° C. After 3hours, a saturated aqueous ammonium solution was added thereto and theresulting mixture was poured into water and extracted with ethylacetate, and the organic layer was dried over anhydrous magnesiumsulfate. The organic layer dried was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtain methyl3-methoxy-1-methylcyclohexanecarboxylate (1.8985 g, 98%, a 4:1 mixtureof isomers).

(c) Synthesis of trans-3-methoxy-1-methylcyclohexanecarboxylic acid

Under a nitrogen atmosphere, a 2M-aqueous lithium hydroxide solution(16.0 ml, 0.0319 mol) was added to a solution of methyl3-methoxy-1-methylcyclohexanecarboxylate (1.9835 g, 0.0106 mol, a 4:1mixture) in methanol (16 ml) at room temperature. After 1 hour, themixture thus obtained was heated to 50° C. After another 3 hours, a2M-aqueous lithium hydroxide solution (0.0213 mol) was further addedthereto. After 1 hour, the reaction solution was adjusted to pH 4 to 5with an aqueous hydrochloric acid solution and extracted withchloroform, and the organic layer was dried over anhydrous magnesiumsulfate. The organic layer dried was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol). The residue purified wasrecrystallized from hexane to obtaintrans-3-methoxy-1-methylcyclohexanecarboxylic acid (1.178 g, 64%) as awhite solid, and cis-3-methoxy-1-methylcyclohexanecarboxylic acid (469.2mg, 26%, a mixture containing 33%trans-3-methoxy-1-methylcyclohexanecarboxylic acid) was obtained as afiltrate residue.

(d) Synthesis of trans-3-methoxy-1-methylcyclohexanecarboamide

Under a nitrogen atmosphere, thionyl chloride (390 mg, 3.27 mmol) andN,N-dimethylformamide (4 drops) were added to a solution oftrans-3-methoxy-1-methylcyclohexanecarboxylic acid (470 mg, 2.73 mmol)in toluene (10 ml) at room temperature, and the resulting mixture washeated to 50° C. After 6 hours, the mixture was heated to 100° C. Afteranother 1 hour, thionyl chloride (1.64 mmol) was further added thereto.After 2 hours, the mixture thus obtained was concentrated under reducedpressure, and a solution of the resulting residue in chloroform (10 ml)was added dropwise to a saturated ammonia-chloroform solution (10 ml) atroom temperature. After 2 hours, the mixture thus obtained was heated to50° C. After 9 hours, the reaction solution was filtered under reducedpressure, and the filtrate was concentrated under reduced pressure andthe resulting residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate→chloroform/methanol) to obtaintrans-3-methoxy-1-methylcyclohexanecarboamide (389.8 mg, 83%).

(e) Synthesis of2-[(3-methoxy-1-methylcyclohexyl)methyl]-1H-isoindole-1,3(2H)dione

Reaction was carried out according to the method described in Example0.649, (b).

(f) Synthesis of2-[(3-hydroxy-1-methylcyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione

Reaction was carried out according to the method described in Example650, (c).

(g) Synthesis of{cis-1-methyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}methylamine

Reaction was carried out according to the method described in Example640, (a), except for using the 4-methyl-1H-indazol-5-ol obtained inExample 402, as a starting material.

IR (neat) cm⁻¹; 2921, 1508, 1221, 941, 816.

EXAMPLE 654 Synthesis oftrans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanecarbonitrile(a) Synthesis of 2,2-dimethyl-5-oxocyclohexanecarbonitrile

Under a nitrogen atmosphere, an aqueous solution (10 ml) of ammoniumchloride (2.37 g, 0.0443 mol) and an aqueous solution (20 ml) ofpotassium cyanide (3.15 g, 0.0483 mol) were added dropwise to a solutionof 4,4-dimethyl-2-cyclohexen-1-one (5.0 g, 0.0403 mol) inN,N-dimethylformamide (30 ml) at room temperature, and the resultingmixture was heated to 70° C. After 2 hours, the reaction solution waspoured into water and extracted with diethyl ether and thendichloromethane. The organic layer was dried over anhydrous magnesiumsulfate. The organic layer dried was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtain2,2-dimethyl-5-oxocyclohexanecarbonitrile (4.033 g, 66%).

(b) Synthesis of cis-5-hydroxy-2,2-dimethylcyclohexanecarbonitrile

Under a nitrogen atmosphere, a solution of2,2-dimethyl-5-oxocyclohexanecarbonitrile (4.0 g, 0.0265 mol) inmethanol (30 ml) was added dropwise to a solution of sodium borohydride(1.00 g, 0.0265 mol) in methanol (40 ml) at 0° C. After 1 hour, sodiumborohydride (0.0133 mol) was further added thereto and the resultingmixture was warmed up to room temperature. After 45 minutes, a saturatedaqueous ammonium chloride solution was added to the reaction solutionand then the methanol was concentrated under reduced pressure. Theresulting aqueous solution was diluted with water and extracted withchloroform, and the organic layer was dried over anhydrous magnesiumsulfate. The organic layer dried was concentrated under reduced pressureand the resulting residue was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtaincis-5-hydroxy-2,2-dimethylcyclohexanecarbonitrile (3.0550 g, 75%).

(c) Synthesis oftrans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanecarbonitrile

Under a nitrogen atmosphere, a solution of90%-cyanomethylenetri-n-butylphosphorane (1.05 g, 4.05 mmol) in toluene(5 ml) was added dropwise to a solution ofcis-5-hydroxy-2,2-dimethylcyclohexanecarbonitrile (500 mg, 3.37 mmol) intoluene (12 ml) at room temperature, followed by adding thereto the4-methyl-1H-indazol-5-ol (507 mg, 3.54 mmol) obtained in Example 402,and the resulting mixture was heated to 100° C. After 4 hours, thereaction solution was concentrated under reduced pressure, and theresulting residue was diluted with chloroform and washed with a1M-aqueous sodium hydroxide solution. The aqueous layer was re-extractedwith chloroform and then the organic layer was dried over anhydrousmagnesium sulfate. The organic layer dried was concentrated underreduced pressure and the resulting residue was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtaintrans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanecarbonitrile(351.1 mg, 46%).

IR (neat) cm⁻¹; 3176, 2954, 1508, 1223, 1094, 945.

EXAMPLE 655 Synthesis oftrans-4-methyl-5-{[3-(1-methyl-1-nitroethyl)cyclohexyl]oxy}-1H-indazole(a) Synthesis of cis-3-(1-methyl-1-nitroethyl)cyclohexanol andtrans-3-(1-methyl-1-nitroethyl)cyclohexanol

Under a nitrogen atmosphere, sodium borohydride (343 mg, 9.07 mmol) wasadded to a solution of 3-(1-methyl-1-nitroethyl)cyclohexanone (1.68 g,9.07 mmol) known in literature in methanol (17 ml) at 0° C. After 45minutes, a saturated aqueous ammonium chloride solution was added to thereaction solution and then the methanol was concentrated under reducedpressure. The resulting aqueous solution was diluted with water andextracted with chloroform, and the organic layer was dried overanhydrous magnesium sulfate. The organic layer dried was concentratedunder reduced pressure and the resulting residue was purified by asilica gel column chromatography (eluent: hexane/ethyl acetate) toobtain cis-3-(1-methyl-1-nitroethyl)cyclohexanol (499.1 mg, 29%),trans-3-(1-methyl-1-nitroethyl)cyclohexanol (259.6 mg, 15%) and amixture of the isomers (55%).

(b) Synthesis oftrans-4-methyl-5-{[3-(1-methyl-1-nitroethyl)cyclohexyl]oxy}-1H-indazole

Reaction was carried out according to the method described in Example654, (c).

IR (neat) cm⁻¹; 3184, 2931, 1533, 1508, 1220, 951, 845.

EXAMPLE 656 Synthesis ofcis-4-[(7-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (a) Synthesis of4-amino-3,5-dimethylphenol

An aqueous solution (4 ml) of sodium nitrite (1.90 g, 27.5 mmol) wasadded to an aqueous solution (20 ml) of sodium sulfanilate dihydrate(5.78 g, 25.0 mmol). The resulting solution was dropped into a beakercontaining concentrated hydrochloric acid (5.1 ml) and ice (30 g), andthe resulting mixture was kept cold in an ice bath for 20 minutes toprepare solution A. An aqueous solution (30 ml) of sodium hydroxide(5.50 g, 138 mmol) and ice (20 g) were added to 3,5-dimethylphenol (3.05g, 250 mmol) to effect dissolution, and then solution A was addeddropwise thereto in an ice bath. The resulting solution was stirred inthe ice bath for 1 hour and then heated to 65° C. to 75° C., and sodiumdithionate (16.8 g, 96.5 mmol) was added thereto until the solution lostits color. The solution was cooled to room temperature and stirred for30 minutes, and the solid formed was collected by filtration and driedto obtain 4-amino-3,5-dimethylphenol (2.46 g, 72%).

(b) Synthesis of [4-(acetylamino)-3,5-dimethylphenyl]acetate

Pyridine (3.30 ml, 40.8 mmol) and acetic anhydride (1.90 ml, 20.1 mmol)were added to a suspension of 4-amino-3,5-dimethylphenol (1.10 g, 8.02mmol) in ethyl acetate (20 ml), and the resulting mixture was stirred at70° C. for 1 hour. The mixture was cooled to room temperature and hexane(60 ml) was added thereto to cause crystallization. The crystals werecollected by filtration and dried to obtain[4-(acetylamino)-3,5-dimethylphenyl]acetate (1.69 g, 96%).

(c) Synthesis of (1-acetyl-7-methyl-1H-indazol-5-yl) acetate

Acetic anhydride (2.20 ml, 23.3 mmol), tetrabutylammonium bromide (124mg, 0.383 mmol), potassium acetate (1.50 g, 15.3 mmol) and isoamylnitrite (1.34 ml, 9.97 mmol) were added in that order to a solution of[4-(acetylamino)-3,5-dimethylphenyl]acetate (1.69 g, 7.64 mmol) in ethylacetate (26 ml), and the resulting mixture was heated under reflux for 4hours. The reaction mixture was cooled to room temperature, poured intowater, and then extracted with ethyl acetate. The extract solution waswashed with a saturated aqueous sodium chloride solution, dried oversodium sulfate, and then distilled under reduced pressure to remove thesolvent. The residue was purified by a silica gel column chromatography(eluent: hexane/ethyl acetate=7:1–5:1) and then washed with diethylether to obtain (1-acetyl-7-methyl-1H-indazol-5-yl)acetate (875 mg,49%).

(d) Synthesis of 7-methyl-1H-indazol-5-ol

A 2N-aqueous lithium hydroxide solution (3.7 ml, 7.4 mmol) was added toa solution of (1-acetyl-7-methyl-1H-indazol-5-yl)acetate (850 mg, 3.66mmol) in methanol-tetrahydrofuran (1:1, 7.4 ml), and the resultingmixture was stirred at room temperature for 30 minutes. A saturatedaqueous ammonium chloride solution was poured into the reactionsolution, followed by extraction with ethyl acetate, and the extractsolution was washed with a saturated aqueous sodium chloride solution,dried over sodium sulfate and then distilled under reduced pressure toremove the solvent. The residue was purified by a silica gel columnchromatography (eluent: chloroform/methanol=100:3) to obtain7-methyl-1H-indazol-5-ol (505 mg, 93%).

(e) Synthesis of cis-4-[(7-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

To a toluene solution (3 ml) of the2-(trans-4-hydroxycyclohexyl)-1H-isoindazole-1,3(2H)-dione (123 mg,0.502 mmol) obtained in Example 323, (a) were added7-methyl-1H-indazol-5-ol (111 mg, 0.749 mmol) andcyanomethylenetri-n-butylphosphorane (226 μl), and the resulting mixturewas stirred at 100° C. for 3 hours. After the solvent was distilled offunder reduced pressure, the residue was diluted with chloroform and thenwashed with a 1N-aqueous sodium hydroxide solution, and the solvent wasdistilled off under reduced pressure. A 30% methylamine-ethanol solution(4 ml) was added to the residue and the resulting mixture was heatedunder reflux for 3 hours. The reaction product thus obtained waspurified by a silica gel column chromatography (eluent:chloroform/methanol/aqueous ammonia=7:1:0.1) to obtaincis-4-[(7-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (70 mg, 57%).

IR (neat) cm⁻¹; 1508, 1163, 1016, 953, 941, 924.

The following compound of Example 657 was synthesized by carrying outreaction according to the method described in Example 656, except forusing 3-ethylphenol as a starting material.

EXAMPLE 657 cis-4-[(3-Methyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 1504, 1448, 1348, 1213, 1205, 1066, 810.

EXAMPLE 658 Synthesis ofcis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (a) Synthesisof (1-acetyl-4,7-dimethyl-1H-indazol-5-yl) acetate

Acetic anhydride (49.8 ml, 0.528 mol), tetrabutylammonium bromide (2.85g, 0.0088 mol), potassium acetate (34.5 g, 0.352 mol) and isoamylnitrite (30.7 ml, 0.229 mol) were added in that order to a solution inethyl acetate (600 ml) of [4-(acetylamino)-2,3,5-trimethylphenyl]acetate(41.4 g, 0.176 mol) synthesized by carrying out reactions according tothe methods described in Example 2, a) and b), except for using2,3,5-trimethylphenol as a starting material. The resulting mixture washeated under reflux for 4 hours. The reaction mixture was cooled to roomtemperature, poured into water, and then extracted with ethyl acetate.The extract solution was washed with a saturated aqueous sodium chloridesolution, dried over sodium sulfate, and then distilled under reducedpressure to remove the solvent. The residue was washed successively withtoluene, diethyl ether and methanol to obtain(1-acetyl-4,7-dimethyl-1H-indazol-5-yl)acetate (20.4 g, 47%). As to thefiltrate, the solvent was distilled off under reduced pressure, and amixture of (4,7-dimethyl-1H-indazol-5-yl)acetate and(6,7-dimethyl-1H-indazol-5-yl)acetate (approximately 1:1, 7.1 g, 20%)was also obtained from a fraction of hexane-ethyl acetate=1:1 by asilica gel column chromatography.

(b) Synthesis of 4,7-dimethyl-1H-indazol-5-ol

A 2N-aqueous lithium hydroxide solution (85 ml, 170 mmol) was added to asolution of (1-acetyl-4,7-dimethyl-1H-indazol-5-yl)acetate (20.3 g, 82.4mmol) in methanol-tetrahydrofuran (1:1, 170 ml) under ice-cooling, andthe resulting mixture was stirred at room temperature for 30 minutes. Asaturated aqueous ammonium chloride solution was poured into thereaction solution, followed by extraction with ethyl acetate, and theextract solution was washed with a saturated aqueous sodium chloridesolution, dried over sodium sulfate and then distilled under reducedpressure to remove the solvent. The residue was washed with acetonitrileby repulping to obtain 4,7-dimethyl-1H-indazol-5-ol (13.0 g, 97%).

(c) Synthesis ofcis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine

To a toluene solution (3 ml) of the2-(trans-4-hydroxycyclohexyl)-1H-isoindazole-1,3(2H)-dione (123 mg,0.502 mmol) obtained in Example 323, (a) were added4,7-dimethyl-1H-indazol-5-ol (122 mg, 0.752 mmol) andcyanomethylenetri-n-butylphosphorane (201 mg, 0.750 mmol), and theresulting mixture was stirred at 100° C. for 5 hours. After the solventwas distilled off under reduced pressure, the residue was diluted withchloroform and then washed with a 1N-aqueous sodium hydroxide solution,and the solvent was distilled off under reduced pressure. A 30%methylamine-ethanol solution (10 ml) was added to the residue and theresulting mixture was heated under reflux for 3 hours. After the solventwas distilled off, a 30% methylamine-ethanol solution (10 ml) was addedto the residue again, and the resulting mixture was heated under refluxfor 7 hours. The solvent was distilled off and then the residue waspurified by a silica gel column chromatography(chloroform/methanol/aqueous ammonia=10:1:0.1) to obtaincis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (54 mg, 42%).

IR (neat) cm⁻¹; 2927, 1676, 1201, 1136, 1001, 949.

EXAMPLE 659 Synthesis ofcis-3-[(4-chloro-6,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (a)Synthesis of 4-chloro-6,7-dimethyl-1H-indazol-5-ol

A 2N-aqueous lithium hydroxide solution (28.6 ml, 57.2 mmol) was addedto a solution of a mixture of (4,7-dimethyl-1H-indazol-5-yl)acetate and(6,7-dimethyl-1H-indazol-5-yl)acetate (approximately 1:1, 5.30 g, 26.0mmol) in methanol (30 ml) under ice-cooling, and the resulting mixturewas stirred at room temperature for 1.5 hours. A saturated aqueousammonium chloride solution was poured into the reaction solution,followed by extraction with ethyl acetate, whereby a mixture of4,7-dimethyl-1H-indazol-5-ol and 6,7-dimethyl-1H-indazol-5-ol (4.31 g,100%) was obtained. To this mixture were added tetrahydrofuran (200 ml)and N-chlorosuccinimide (1.74 g, 13.0 mmol), and the resulting mixturewas stirred at 50° C. for 3 hours. The reaction solution was poured intowater to terminate the reaction, and was extracted with ethyl acetate.The extract solution was washed with a saturated aqueous sodium chloridesolution, dried over sodium sulfate, and then distilled under reducedpressure to remove the solvent, whereby a crude product was obtained.The crude product was washed three times with methanol to obtain4-chloro-6,7-dimethyl-1H-indazol-5-ol (440 mg). On the other hand, thesolvent of the filtrate was distilled off under reduced pressure andthen the residue was purified by a silica gel column chromatography(hexane/ethyl acetate=2:1) to obtain4-chloro-6,7-dimethyl-1H-indazol-5-ol (980 mg, 1.42 g in total, 56%).

(b) Synthesis ofcis-3-[(4-chloro-6,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine

To a toluene solution (4 ml) of the2-(trans-3-hydroxycyclohexyl)-1H-isoindazole-1,3(2H)-dione (246 mg, 1.00mmol) obtained in Example 385, (b) were added4-chloro-6,7-dimethyl-1H-indazol-5-ol (197 mg, 1.00 mmol) andcyanomethylenetri-n-butylphosphorane (349 mg, 1.30 mmol), and theresulting mixture was stirred at 100° C. for 3.5 hours. After thesolvent was distilled off under reduced pressure, the residue wasdiluted with chloroform and then washed with a 1N-aqueous sodiumhydroxide solution, and the solvent was distilled off under reducedpressure. A 30% methylamine-ethanol solution (5 ml) was added to theresidue and the resulting mixture was heated under reflux for 2 hours.After the solvent was distilled off, the residue was purified by apreparative thin-layer silica gel chromatography (eluent:chloroform/methanol/aqueous ammonia=7:1:0.1) to obtaincis-3-[(4-chloro-6,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (19mg, 7%).

IR (neat) cm⁻¹; 2937, 1473, 1352, 1296, 1074, 995, 933.

The following compounds of Examples 660 and 661 were synthesized bycarrying out reaction according to the method described in Example 658.

EXAMPLE 660 cis-3-[(4,7-Dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 2931, 1523, 1450, 1356, 1323, 1099, 1001, 937.

EXAMPLE 661 trans-4-[(4,7-Dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 1525, 1227, 1109, 1086, 941, 937, 850.

EXAMPLE 662 Synthesis ofcis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine

A 36% aqueous formalin solution (161 μl, 1.93 mmol) was added to amethanolic solution (2 ml) of thecis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.386mmol) obtained in Example 658, and the resulting mixture was stirred atroom temperature for 1 hour. Sodium cyanoborohydride (51 mg, 0.771 mmol)and acetic acid (110 μl, 1.92 mmol) were added thereto, and theresulting mixture was stirred at room temperature for 18 hours. Themethanol was removed by the use of nitrogen gas andchloroform-1N-aqueous sodium hydroxide solution was added to theresidue, followed by extraction with chloroform. The extract solutionwas washed with a saturated aqueous sodium chloride solution, dried oversodium sulfate, and then distilled under reduced pressure to remove thesolvent, whereby a crude product was obtained. The crude product waspurified by a preparative thin-layer silica gel chromatography(chloroform/methanol/aqueous ammonia=7:1:0.1) to obtaincis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine(77 mg, 69%).

IR (neat) cm⁻¹; 1525, 1327, 1227, 1109, 1032, 935.

The following compounds of Examples 663 and 664 were synthesized bycarrying out reaction according to the method described in Example 662,except for using thecis-3-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained inExample 660, as a starting material.

EXAMPLE 663cis-N-{3-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine

IR (neat) cm⁻¹; 2935, 1522, 1323, 1099, 1007, 949.

EXAMPLE 664cis-N-benzyl-N-{3-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 2935, 1525, 1452, 1356, 1323, 1196, 1097, 1007, 953.

The following compound of Example 665 was synthesized by carrying outreaction according to the method described in Example 662.

EXAMPLE 665cis-N-benzyl-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 2931, 1523, 1450, 1442, 1323, 1101, 937.

The following compounds of Examples 666 and 667 were synthesized bycarrying out reaction according to the method described in Example 662,except for using thetrans-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained inExample 661, as a starting material.

EXAMPLE 666trans-N-{4-[(4,7-Dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine

IR (neat) cm⁻¹; 1520, 1450, 1093, 1055, 1036, 953, 928.

EXAMPLE 667trans-N-benzyl-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 1525, 1452, 1325, 1201, 1103, 944.

EXAMPLE 668 Synthesis ofcis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

Triethylamine (108 μl, 0.775 mmol), propionic acid (32 μl, 0.429 mmol),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (83 mg,0.433 mmol) and 1-hydroxybenzotriazole (58 mg, 0.429 mmol) were added inthat order to a dimethylformamide solution (2 ml) of thecis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.386mmol) obtained in Example 658, and the resulting mixture was stirred atroom temperature for 20 hours. The reaction was terminated by theaddition of water, followed by extraction with ethyl acetate-toluene(1:1). The extract solution was washed with a saturated aqueous sodiumchloride solution, dried over sodium sulfate, and then distilled underreduced pressure to remove the solvent, whereby a crude product wasobtained. The crude product was purified by a silica gel chromatography(eluent: chloroform/methanol=100:2) to obtaincis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (134mg, 100%).

IR (neat) cm⁻¹; 1641, 1541, 1524, 1325, 1128, 1103, 943.

The following compound of Example 669 was synthesized by carrying outreaction according to the method described in Example 668, except forusing the cis-3-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 660, as a starting material.

EXAMPLE 669cis-N-{3-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

IR (neat) cm⁻¹; 1639, 1541, 1522, 1323, 1101, 1003, 949.

The following compound of Example 670 was synthesized by carrying outreaction according to the method described in Example 668, except forusing the trans-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 661, as a starting material.

EXAMPLE 670trans-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

IR (neat) cm⁻¹; 1632, 1537, 1525, 1325, 1200, 1111, 1082, 943.

EXAMPLE 671 Synthesis ofcis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylamine

Lithium aluminum hydride (70 mg, 1.84 mmol) was added to atetrahydrofuran solution (5 ml) of thecis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (116mg, 0.368 mmol) obtained in Example 668, and the resulting mixture washeated under reflux for 5 hours. After the reaction solution was dilutedwith 10 ml of tetrahydrofuran, the reaction was terminated by carefuladdition of water (76 μl), a 4N-aqueous sodium hydroxide solution (76μl) and water (230 μl) in that order under ice-cooling. The reactionsolution thus treated was filtered by the use of Celite and the solventwas distilled off under reduced pressure to obtain a crude product. Thecrude product was purified by a preparative thin-layer silica gelchromatography (chloroform/methanol/aqueous ammonia=7:1:0.1) to obtaincis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylamine(64 mg, 58%).

IR (neat) cm⁻¹; 1522, 1325, 1232, 1213, 1105, 939, 920.

The following compound of Example 672 was synthesized by carrying outreaction according to the method described in Example 671, except forusing thecis-N-{3-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamideobtained in Example 669, as a starting material.

EXAMPLE 672cis-N-{3-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylamine

IR (neat) cm⁻¹; 1524, 1454, 1356, 1323, 1099, 1003, 951.

The following compound of Example 673 was synthesized by carrying outreaction according to the method described in Example 671, except forusing thetrans-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamideobtained in Example 670, as a starting material.

EXAMPLE 673trans-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylamine

IR (neat) cm⁻¹; 1525, 1327, 1200, 1107, 941.

EXAMPLE 674 Synthesis of2-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione

Diisopropyl dicarboxylate (4.85 g, 24.0 mmol) was added dropwise to amixture of the 5-hydroxy-4-methyl-1H-indazole (2.96 g, 20.0 mmol)obtained in Example 402, the2-(trans-4-hydroxycyclohexyl)-1H-isoinzole-1,3(2H)-dione (4.90 g, 20.0mmol) obtained in Example 323, (a), triphenylphosphine (5.77 g, 22.0mmol) and tetrahydrofuran (120 ml) under ice-cooling. After 30 minutes,the mixture thus obtained was warmed up to room temperature and stirredovernight. After the reaction solution was concentrated, a 1N-aqueoussodium hydroxide solution (200 ml) was added to the residue, followed byextraction with chloroform (120 ml) (three times). The organic layer waswashed with a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. The solvent was distilled off and the residue oil waspurified by a silica gel column chromatography (hexane/ethyl acetate=2:1to 1:1) to obtain2-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(1.76 g, 23%).

NMR (DMSO-d₆) δ; 1.45–1.72 (4H, m), 2.03 (2H, d, J=14.1 Hz), 2.55–2.67(5H, m), 4.05–4.17 (1H, m), 4.59 (1H, s), 7.16 (1H, d, J=9.0 Hz), 7.19(1H, d, J=9.2 Hz), 7.75–7.88 (4H, m), 8.03 (1H, s), 12.85 (1H, s).

EXAMPLE 675 Synthesis ofcis-4-[(1,4-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (a) Synthesisof2-{cis-4-[(1,4-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dioneand2-{cis-4-[(2,4-dimethyl-2H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione

Potassium carbonate (55 mg, 0.398 mmol) and then methyl iodide (15 μl,0.241 mmol) were added to a suspension of thecis-2-[4-(4-methyl-1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione(75 mg, 0.200 mmol) obtained in Example 674 in dimethylformamide (1 ml),and the resulting mixture was stirred at 60° C. for 24 hours. Asaturated aqueous ammonium chloride solution was added thereto, followedby extraction with ethyl acetate. The extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent. By asilica gel column chromatography,2-{cis-4-[(1,4-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione(31 mg, 40%) was obtained from a fraction of hexane-ethyl acetate=2:1,and2-{cis-4-[(2,4-dimethyl-2H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione(13 mg, 17%) was obtained from a fraction of hexane-ethyl acetate=1:1.

(b) Synthesis ofcis-4-[(1,4-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine

A 30% methylamine-ethanol solution (3 ml) was added to2-{cis-4-[(1,4-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione(30 mg, 0.077 mmol), and the resulting mixture was heated under refluxfor 2 hours. The solvent was distilled off under reduced pressure andthe residue was purified by a silica gel column chromatography(chloroform/methanol/aqueous ammonia=100:10:1) to obtaincis-4-[(1,4-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (16 mg, 80%).

¹H-NMR (CD₃OD) δ; 1.68 (6H, m), 2.05 (2H, m), 2.48 (3H, s), 2.82 (1H,m), 4.00 (3H, s), 4.43 (1H, m), 7.20 (1H, m), 7.29 (1H, m), 7.94 (1H,s).

EXAMPLE 676 Synthesis ofcis-4-[(2,4-dimethyl-2H-indazol-5-yl)oxy]cyclohexanamine

A 30% methylamine-ethanol solution (2 ml) was added to the2-{cis-4-[(2,4-dimethyl-2H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione(12 mg, 0.031 mmol) obtained in Example 675, (a), and the resultingmixture was heated under reflux for 2 hours. The solvent was distilledoff under reduced pressure and the residue was purified by a silica gelcolumn chromatography (chloroform/methanol/aqueous ammonia=100:10:1) toobtain cis-4-[(2,4-dimethyl-2H-indazol-5-yl)oxy]cyclo-hexanamine (8 mg,100%).

¹H-NMR (CD₃OD) δ; 1.71 (6H, m), 2.04 (2H, m), 2.42 (3H, s), 2.86 (1H,m), 4.16 (3H, s), 4.16 (1H, m), 7.14 (1H, m), 7.35 (1H, m), 8.09 (1H,s).

The following compounds of Examples 677 to 680 were synthesized bycarrying out reactions according to the methods described in Examples675 and 676.

EXAMPLE 677 cis-4-[(1-Butyl-4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (CD₃OD) δ; 0.91 (3H, t, J=7.3 Hz), 1.27 (2H, sex, J=7.4 Hz), 1.66(6H, m), 1.83 (2H, qu, J=7.4 Hz), 2.02 (2H, m), 2.48 (3H, s), 2.78 (1H,m), 4.34 (2H, t, J=7.0 Hz), 4.41 (1H, m), 7.16 (1H, d, J=9.0 Hz), 7.30(1H, d, J=9.2 Hz), 7.94 (1H, s).

EXAMPLE 678 cis-4-[(2-Butyl-4-methyl-2H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (CD₃OD) δ; 0.95 (3H, t, J=7.4 Hz), 1.31 (2H, six, J=7.5 Hz), 1.67(6H, m), 1.95 (2H, qu, J=7.3 Hz), 2.02 (2H, m), 2.43 (3H, s), 2.8 (1H,m), 4.39 (2H, t, J=7.2 Hz), 4.40 (1H, m), 7.12 (1H, d, J=9.2 Hz), 7.37(1H, d, J=9.3 Hz), 8.12 (1H, s).

EXAMPLE 679cis-4-{[4-Methyl-1-(2,2,2-trifluoromethyl)-1H-indazol-5-yl]oxy}cyclohexanamine

¹H-NMR (CD₃OD) δ; 1.67 (6H, m), 2.05 (2H, m), 2.50 (3H, s), 2.79 (1H,m), 4.46 (1H, m), 5.12 (2H, q, J=8.8 Hz), 7.23 (1H, d, J=9.0 Hz), 7.38(1H, d, J=9.2 Hz), 8.07 (1H, s).

EXAMPLE 680cis-4-{[4-Methyl-2-(2,2,2-trifluoromethyl)-2H-indazol-5-yl]oxy}cyclohexanamine

¹H-NMR (CD₃OD) δ; 1.66 (6H, m), 2.03 (2H, m), 2.44 (3H, s), 2.77 (1H,m), 4.44 (1H, m), 5.20 (2H, q, J=8.6 Hz), 7.20 (1H, d, J=9.3 Hz), 7.43(1H, d, J=9.4 Hz), 8.26 (1H, s).

EXAMPLE 681 Synthesis ofcis-4-[(3-bromo-4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (a)Synthesis of2-{cis-4-[(3-bromo-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione

A 2N-aqueous sodium hydroxide solution (1.5 ml) was added to asuspension of thecis-2-[4-(4-methyl-1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione(375 mg, 0.999 mmol) obtained in Example 674 in dioxane (3 ml). Asolution of bromine (36 μl, 0.699 mmol) in a 2N-aqueous sodium hydroxidesolution (1.5 ml) was added thereto under ice-cooling, and the resultingmixture was stirred at the same temperature for 2 hours. A saturatedaqueous sodium hydrogesulfite solution (5 ml) was added thereto, and thewater was removed as an azeotrope with ethanol. Ethanol (30 ml) andp-toluenesulfonic acid monohydrate (38 mg, 0.200 mmol) were added to theresidue, and the resulting mixture was heated under reflux. After 2hours, p-toluenesulfonic acid monohydrate (152 mg, 0.80 mmol) was addedthereto, followed by heating under reflux for another 2 hours. Thesolvent was distilled off under reduced pressure and ethyl acetate wasadded to the residue, followed by washing with 1N-hydrochloric acid. Theresidue thus treated was washed with water, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent. To theresulting residue was added 1,2-dichloroethane (5 ml), followed byadding thereto 2H-3,4-dihydropyran (140 μl, 1.53 mmol) andp-toluenesulfonic acid monohydrate (38 mg, 0.200 mmol), and theresulting mixture was stirred for 1 week. The solvent was distilled offunder reduced pressure and the residue was purified by a silica gelcolumn chromatography (hexane/ethyl acetate=4:1) to obtain2-{cis-4-[(3-bromo-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione(162 mg, 30%).

(b) Synthesis ofcis-4-[(3-bromo-4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Trifluoroacetic acid (1.8 ml) was added to a dichloromethane solution(7.2 ml) of2-{cis-4-[(3-bromo-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindazole-1,3(2H)-dione(154 mg, 0.286 mmol), and the resulting mixture was stirred at roomtemperature for 1 hour. The reaction was terminated by the use of asaturated aqueous sodium hydrogencarbonate solution, followed byextraction with ethyl acetate. The extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent. A 30%methylamine-ethanol solution (10 ml) was added to the residue and theresulting mixture was heated under reflux for 3 hours. The solvent wasdistilled off and the residue was purified by a silica gel columnchromatography (chloroform/methanol/aqueous ammonia=10:1:0.1) to obtaincis-4-[(3-bromo-4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (70 mg,75%).

¹H-NMR (CD₃OD) δ; 1.71 (6H, m), 2.06 (2H, m), 2.69 (3H, s), 2.93 (1H,m), 4.44 (1H, m), 7.19 (1H, d, J=9.0 Hz), 7.29 (1H, d, J=9.0 Hz).

EXAMPLE 682 Synthesis of 4-ethyl-1H-indazol-5-ol (a) Synthesis of1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-4-vinyl-1H-indazole

A mixture of the4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(2.00 g, 5.25 mmol) obtained in Example 607, (a), tributylvinyltin (1.83g, 5.77 mmol) and tetrakis(triphenylphosphine)palladium (606 mg, 0.524mmol) was stirred in toluene (26.0 ml) for 5 hours with heating underreflux while maintaining the temperature.Tetrakis(triphenylphosphine)palladium (202 mg, 0.171 mmol) was furtheradded thereto and the resulting mixture was stirred for another 3 hourswith heating under reflux while maintaining the temperature. Aftercooling, the reaction mixture was diluted with ethyl acetate and 10%aqueous ammonia was added thereto and stirred. The resulting mixture wasfiltered by the use of Celite and the filtrate was partitioned by usingwater and ethyl acetate. The organic layer was washed with a saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, and then filtered, and the filtrate was concentrated underreduced pressure to obtain a crude product. The crude product waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-4-vinyl-1H-indazole(1.35 g, 78%).

(b) Synthesis of4-ethyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole

To a solution of1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-4-vinyl-1H-indazole(1.35 g, 4.11 mmol) in ethyl acetate (40 ml) was added10%-palladium/carbon (containing 50% water, 50 mg), and the resultingmixture was stirred for 6 hours at ordinary temperature and atmosphericpressure under a hydrogen atmosphere. To the mixture was further added10%-palladium/carbon (containing 50% water, 670 mg), and stirred foranother 1.5 hours. The reaction mixture was filtered by the use ofCelite and washed with methanol, and then the filtrate was concentratedunder reduced pressure to obtain4-ethyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(1.41 g).

(c) Synthesis of 4-ethyl-1H-indazol-5-ol

In a mixed solvent of tetrahydrofuran (5.0 ml) and water (2.5 ml) wassuspended4-ethyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(1.40 g), followed by adding thereto trifluoroacetic acid (10.0 ml), andthe resulting mixture was stirred for 2.5 hours while being maintainedat room temperature. The reaction mixture was neutralized with a2N-aqueous sodium hydroxide solution and extracted with ethyl acetate,and the extract solution was dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure to obtaina crude product. The crude product was purified by a silica gel columnchromatography (eluent: chloroform/ethyl acetate) to obtain4-ethyl-1H-indazol-5-ol (314 mg, 47%) as a white solid.

¹H-NMR (DMSO-d₆) δ; 1.15 (3H, t, J=7.4 Hz), 2.80 (2H, q, J=7.4 Hz), 6.92(1H, d, J=8.8 Hz), 7.15 (1H, d, J=8.8 Hz), 7.92 (1H, s), 8.72 (1H, s),12.69 (1H, brs).

The following compounds of Examples 683 and 684 were synthesized bycarrying out reaction according to the method described in Example 407,except for using the 4-ethyl-1H-indazol-5-ol obtained in Example 682, asa starting material.

EXAMPLE 683 4-Ethyl-5-(piperidin-4-yloxy)-1H-indazole

¹H-NMR (CDCl₃) δ; 1.30 (3H, t, J=7.5 Hz), 1.65–1.77 (2H, m), 2.00–2.07(2H, m), 2.66–2.75 (2H, m), 2.98 (2H, q, J=7.5 Hz), 3.14–3.21 (2H, m),4.23 (1H, m), 7.12 (1H, d, J=8.8 Hz), 7.26 (1H, dd, J=8.8, 0.92 Hz),8.06 (1H, d, J=0.92 Hz).

EXAMPLE 684 5-(Azepan-4-yloxy)-4-ethyl-1H-indazole

¹H-NMR (CDCl₃) δ; 1.28 (3H, t, J=7.5 Hz), 1.54–1.67 (1H, m), 1.82–2.20(5H, m), 2.82–3.12 (6H, m), 4.45 (1H, m), 7.07 (1H, d, J=9.0 Hz), 7.24(1H, dd, J=9.0, 1.0 Hz), 8.05 (1H, d, J=1.0 Hz).

EXAMPLE 685 Synthesis of 4-isopropyl-1H-indazol-5-ol (a) Synthesis of2-[1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-yl]propan-2-ol

A solution of the4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(3.81 g, 10.0 mmol) obtained in Example 607, (a) in tetrahydrofuran (50ml) was cooled to −78° C., and 1.57M n-butyllithium (7.64 ml, 12.0 mmol)was added dropwise thereto. After the resulting mixture was kept cold at−78° C. for 30 minutes, acetone (1.10 ml, 15.0 mmol) was added dropwisethereto and the resulting mixture was stirred for 1 hour while beingkept cold at −78° C. The mixture was warmed up to room temperature andstirred for another 1 hour while maintaining the temperature. Aftercooling, a saturated aqueous ammonium chloride solution was addedthereto and stirred, followed by partition and extraction with ethylacetate. The organic layer was washed with a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, and thenfiltered, and the filtrate was concentrated under reduced pressure toobtain a crude product. The crude product was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain2-[1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-yl]propan-2-ol(2.46 g, 68%).

(b) Synthesis of4-isopropyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazoleand 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol

In an autoclave, 10%-palladium/carbon (containing 50% water, 1.0 g) wasadded to a solution of2-[1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazol-4-yl]propan-2-ol(1.92 g, 5.33 mmol) in ethanol (26 ml), and the resulting mixture wasstirred at 60° C. for 5 hours under a hydrogen atmosphere of 30atmospheric pressure. The reaction mixture was filtered by the use ofCelite and washed with methanol, and then the filtrate was concentratedunder reduced pressure to obtain a crude product. The crude product waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate) to obtain4-isopropyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(301 mg, 16%) and 4-isopropyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol(586 mg, 42%).

(c) Synthesis of 4-isopropyl-1H-indazol-5-ol

A mixture of4-isopropyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(301 mg, 0.871 mmol) and4-isopropyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (586 mg, 2.25mmol) was made into a solution of the mixture in dichloromethane (26ml), followed by adding thereto trifluoroacetic acid (6.5 ml), and theresulting mixture was stirred for 4 hours while being maintained at roomtemperature. The reaction solution was diluted with ethyl acetate,neutralized with a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate, and the extract solution was driedover anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated under reduced pressure to obtain a crude product. The crudeproduct was purified by a silica gel column chromatography (eluent:chloroform/ethyl acetate) to obtain 4-isopropyl-1H-indazol-5-ol (430 mg,78%).

¹H-NMR (DMSO-d₆) δ; 1.48 (6H, d, J=7.2 Hz), 3.59 (1H, sep, J=7.2 Hz),6.95 (1H, d, J=8.8 Hz), 7.20 (1H, d, J=8.8 Hz), 8.16 (1H, s).

The following compounds of Examples 686 to 689 were synthesized bycarrying out reaction according to the method described in Example 640,(a), except for using the 4-isopropyl-1H-indazol-5-ol obtained inExample 685, as a starting material.

EXAMPLE 686 trans-3-[(4-Isopropyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 2933, 2866, 1230, 943, 914.

EXAMPLE 687 cis-3-[(4-Isopropyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 2931, 2862, 1221, 1030, 941, 908.

EXAMPLE 688 trans-4-[(4-Isopropyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 2933, 2864, 1225, 1045, 943, 908.

EXAMPLE 689 cis-4-[(4-Isopropyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 2931, 2866, 1223, 1036, 939, 906.

EXAMPLE 690 Synthesis of 5-hydroxy-1H-indazole-4-carbonitrile (a)1-Tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole-4-carbonitrile

A mixture of the4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole(763 mg, 2.00 mmol) obtained in Example 607, (a), copper(I) iodide (76mg, 0.40 mmol), sodium cyanide (412 mg, 8.40 mmol) andtetrakis(triphenylphosphine)palladium (240 mg, 0.208 mmol) was stirredin propionitrile (10.0 ml) for 16 hours with heating under reflux whilemaintaining the temperature. After cooling, the reaction mixture wasdiluted with ethyl acetate and filtered by the use of Celite, and thefiltrate was partitioned by the use of water and ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, and then filtered, andthe filtrate was concentrated under reduced pressure to obtain a crudeproduct. The crude product was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtain1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole-4-carbonitrile(254 mg, 39%).

(b) 5-Hydroxy-1H-indazole-4-carbonitrile

Trifluoroacetic acid (1.5 ml) was added dropwise to a solution of1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole-4-carbonitrile(227 mg, 0.693 mmol) in dichloromethane (6.5 ml) at room temperature,and the resulting mixture was stirred for 1.5 hours while beingmaintained at room temperature. The reaction solution was diluted withethyl acetate and adjusted to pH 7 with a saturated aqueous sodiumhydrogencarbonate solution, followed by partition and extraction. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, and then filtered, andthe filtrate was concentrated under reduced pressure to obtain a crudeproduct. The crude product was purified by a silica gel columnchromatography (eluent: hexane/ethyl acetate) to obtain5-hydroxy-1H-indazole-4-carbonitrile (108 mg, 98%).

IR (neat) cm⁻¹; 3404, 2224, 1147, 937, 928.

The following compound of Example 691 was synthesized by carrying outreaction according to the method described in Example 407, except forusing the 5-hydroxy-1H-indazole-4-carbonitrile obtained in Example 690,as a starting material.

EXAMPLE 691 5-(Azepan-4-yloxy)-1H-indazole-4-carbonitrile

IR (neat) cm⁻¹; 2933, 2211, 1495, 1313, 1246, 931.

The following compounds of Examples 692 to 695 were synthesized bycarrying out reaction according to Example 640, (a), except for usingthe 5-hydroxy-1H-indazole-4-carbonitrile obtained in Example 690, as astarting material.

EXAMPLE 692 trans-5-[(3-Aminocyclohexyl)oxy]-1H-indazole-4-carbonitrile

IR (neat) cm⁻¹; 2933, 2218, 1497, 1308, 1240, 941.

EXAMPLE 693 cis-5-[(3-Aminocyclohexyl)oxy]-1H-indazole-4-carbonitrile

IR (neat) cm⁻¹; 2935, 2216, 1497, 1311, 1242, 945.

EXAMPLE 694 trans-5-[(4-Aminocyclohexyl)oxy]-1H-indazole-4-carbonitrile

IR (neat) cm⁻¹; 2922, 2208, 1489, 1313, 1248, 935.

EXAMPLE 695 cis-5-[(4-Aminocyclohexyl)oxy]-1H-indazole-4-carbonitrile

IR (neat) cm⁻¹; 2925, 2213, 1487, 1053, 1011, 930.

EXAMPLE 696 Synthesis of 5-(azepan-4-yloxy)-1H-indazole-4-carboxamide

Potassium hydroxide (powder, 100 mg) was added to a solution of the5-(azepan-4-yloxy)-1H-indazole-4-carbonitrile (9.2 mg, 0.036 mmol)obtained in Example 691 in t-butanol (2 ml) at room temperature, and theresulting mixture was stirred for 30 hours with heating under refluxwhile maintaining the temperature. The reaction mixture was diluted withethanol and filtered, and the filtrate was concentrated under reducedpressure to obtain a crude product. The crude product was purified by asilica gel column chromatography (eluent: chloroform/methanol/28%aqueous ammonia) to obtain 5-(azepan-4-yloxy)-1H-indazole-4-carboxamide(2.5 mg, 25%).

MS: m/z=275 (M+1)

The following compound of Example 697 was synthesized by carrying outreaction according to the method described in Example 696.

EXAMPLE 697 cis-5-[(3-Aminocyclohexyl)oxy]-1H-indazole-4-carboxamide

MS: m/z=275 (M+1)

EXAMPLE 698 Synthesis of2-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-1H-isoindole-1,3(2H)-dione

Under nitrogen, the 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione(1.23 g, 5.01 mmol) obtained in Example 385, (b), the4-methoxy-1H-indazol-5-ol (0.906 g, 5.52 mmol) obtained in Example 469and 90%-cyanomethylenetri-n-butylphosphorane (161 g, 6.02 mmol) weredissolved in toluene (20 ml), and the resulting solution was heatedunder reflux for 5 hours. The reaction solution was cooled to roomtemperature and water and a 1N-aqueous sodium hydroxide solution wereadded thereto. The resulting solution was separated by the addition oftoluene and the desired compound was extracted from the aqueous layerwith toluene. The combined toluene layer was washed with a saturatedaqueous sodium chloride solution, dried by the addition of anhydrousmagnesium sulfate, and then filtered. The solvent was distilled offunder reduced pressure and the concentration residue thus obtained waspurified by a silica gel column chromatography (eluent: n-hexane/ethylacetate=2/1, 1/1) to obtain2-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-1H-isoindole-1,3(2H)-dione(1.29 g, yield 66%).

IR (neat) cm⁻¹; 3373, 2949, 2360, 1697, 1508, 1375, 1350, 1238, 1219,1076, 1035, 1018.

The compound of Example 699 was synthesized by carrying out reactionaccording to the method described in Example 698, except for using thetrans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 385, (b), as a starting material.

EXAMPLE 6992-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-1H-isoindole-1,3(2H)-dione

IR (neat) cm⁻¹; 2358, 2343, 1701, 1508, 1373, 1349, 1228, 1087, 1033.

EXAMPLE 700 Synthesis ofN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-dimethylaminemonohydrochloride

Under nitrogen, thecis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.383mmol) obtained in Example 583 and 36%-formaldehyde (160 mg, 1.91 mmol)were suspended in a mixture of acetonitrile (2 ml) and methanol (2 ml),and the resulting suspension was stirred at room temperature for 20minutes. Then, sodium cyanoborohydride (48 mg, 0.765 mmol) and aceticacid (0.2 ml) were added thereto, and the resulting mixture was stirredat room temperature for 5 hours. The reaction mixture was diluted withchloroform, washed successively with a 1N-aqueous sodium hydroxidesolution, water and a saturated aqueous sodium chloride solution, driedby the addition of anhydrous magnesium sulfate, and then filtered. Thesolvent was distilled off under reduced pressure and the resultingconcentration residue was purified by a silica gel column chromatography(eluent: chloroform/methanol=20/1, chloroform/methanol/aqueousammonia=20/1/0.1). The residue purified was dissolved in isopropylalcohol and a 4N-hydrochloric acid/dioxane solution was added theretoand stirred. Then, the solvent was distilled off under reduced pressureto obtainN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-dimethylaminemonohydrochloride (43 mg, yield 34%).

IR (neat) cm⁻¹; 3600–2100, 1508, 1380, 1352, 1230, 1089, 1035, 962.

EXAMPLE 701 Synthesis ofN-ethyl-N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]aminemonohydrochloride (a) Synthesis ofN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]acetamide

Under nitrogen, thecis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.383mmol) obtained in Example 583 was suspended in N,N-dimethylformamide (3ml), and acetic acid (25 μl, 0.421 mmol) and triethylamine (107 μl,0.765 mmol) were added thereto, followed by adding thereto1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide mono-hydrochloride (81mg, 0.421 mmol) and 1-hydroxybenzotriazole (57 mg, 0.421 mmol). Theresulting mixture was stirred at room temperature for 21 hours.

A 1N-aqueous sodium hydroxide solution was added thereto and stirred for30 minutes, followed by extraction with ethyl acetate (three times). Thecombined ethyl acetate layer was washed with a saturated aqueous sodiumchloride solution, dried by the addition of anhydrous magnesium sulfate,and then filtered. The solvent was distilled off under reduced pressureand the concentration residue thus obtained was purified by a silica gelcolumn chromatography (eluents: n-hexane/ethyl acetate=1/4 andchloroform/methanol=10/1) to obtainN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]acetamide (106 mg,yield 91%).

(b) Synthesis ofN-ethyl-N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]aminemonohydrochloride

Under nitrogen,N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]acetamide (106 mg,0.349 mmol) was dissolved in tetrahydrofuran (5 ml), followed by addingthereto lithium aluminum hydride (27 mg, 0.699 mmol), and the resultingmixture was stirred with heating under reflux for about 4 hours.

Under ice-cooling, the reaction solution was diluted withtetrahydrofuran, and water (68 μl) was added thereto and stirred, andthen a 4N-aqueous sodium hydroxide solution (68 μl) and water (200 μl)were added thereto and stirred. The solid was filtered off and thesolvent was distilled off under reduced pressure. The resultingconcentration residue was purified by a silica gel column chromatography(eluent: acetonitrile/aqueous ammonia=100/0, 100/2, 100/5). The residuepurified was dissolved in isopropyl alcohol, followed by adding theretoa 4N-hydrochloric acid/dioxane solution, and the resulting mixture wasconcentrated to dryness to obtainN-ethyl-N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]aminemonohydrochloride (40 mg, yield 35%).

IR (neat) cm⁻¹; 3600–2300, 1583, 1508, 1452, 1382, 1350, 1228, 1091,1036.

EXAMPLE 702 Synthesis ofN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N-propylamine (a)Synthesis ofN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide

Under nitrogen, thecis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.383mmol) obtained in Example 583 was suspended in N,N-dimethylformamide (2ml), and propionic acid (31 μl, 0.421 mmol) and triethylamine (107 μl,0.765 mmol) were added thereto, followed by adding thereto1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide mono-hydrochloride (81mg, 0.421 mmol) and 1-hydroxybenzotriazole (57 mg, 0.421 mmol). Theresulting mixture was stirred at room temperature for 24 hours. Waterwas added to the reaction mixture, followed by extraction with ethylacetate (three times). The combined ethyl acetate layer was washed witha saturated aqueous sodium chloride solution, dried by the addition ofanhydrous magnesium sulfate, and then filtered. The solvent wasdistilled off under reduced pressure and the resulting concentrationresidue was purified by a silica gel column chromatography (eluent:chloroform/methanol=100/0, 100/2) to obtainN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide (141 mg,yield 116%) as light-yellow tar.

(b) Synthesis ofN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N-propylamine

Under nitrogen,N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide (141 mg,0.444 mmol) was dissolved in tetrahydrofuran (7 ml), followed by addingthereto lithium aluminum hydride (84 mg, 2.22 mmol), and the resultingmixture was stirred with heating under reflux for about 2 hours. Underice-cooling, the reaction solution was diluted with tetrahydrofuran, andwater (84 μl) was added thereto and stirred, and then a 4N-aqueoussodium hydroxide solution (84 μl) and water (250 μl) were added theretoand stirred. The solid was filtered off and the solvent was distilledoff under reduced pressure. The resulting concentration residue waspurified by a silica gel column chromatography (eluent:acetonitrile/aqueous ammonia=100/0, 100/2, 100/5) to obtainN-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N-propylamine (57mg, yield 42.3%) as colorless tar.

IR (neat) cm⁻¹; 2933, 2856, 2360, 1508, 1388, 1348, 1218, 1095, 1034,920.

The following compounds of Examples 703 and 704 were synthesized bycarrying out reaction according to the method described in Example 702,(a).

EXAMPLE 703N-[cis-4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]acetamide

IR (neat) cm⁻¹; 3241, 2944, 2358, 1616, 1560, 1506, 1400, 1336, 1325,1257, 1225, 1124, 1101, 1039, 941, 908.

EXAMPLE 704N-[cis-4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide

IR (neat) cm⁻¹; 3300–270, 2360, 1637, 1506, 1340, 1252, 1227, 1120,1095, 929.

The following compound of Example 705 was synthesized by carrying outreaction according to the method described in Example 702, (b), exceptfor using theN-[cis-4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]acetamide obtainedin Example 703, as a starting material.

EXAMPLE 705N-ethyl-N-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]amine

IR (neat) cm⁻¹; 2950–2300, 1495, 1350, 1290, 1225, 1209, 1021, 970, 923.

The following compound of Example 706 was synthesized by carrying outreaction according to the method described in Example 702, (b), exceptfor using theN-[cis-4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide obtainedin Example 704, as a starting material.

EXAMPLE 706N-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N-propylamine

IR (neat) cm⁻¹; 3153, 2931, 1506, 1348, 1221, 1091, 939.

The following compound of Example 707 was synthesized by carrying outreaction according to the method described in Example 700, except forusing a free form of thecis-4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexanamine monohydrochlorideobtained in Example 585, as a starting material.

EXAMPLE 707N-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-dimethylamine

IR (neat) cm⁻¹; 2940, 2651, 2360, 1498, 1387, 1351, 1232, 1033, 1018,933.

The following compounds of Examples 708 to 712 were synthesized bycarrying out reaction according to the method described in Example 391,except for using thecis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example411, as a starting material.

EXAMPLE 708N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}butanamide

IR (neat) cm⁻¹; 3278, 3178, 2948, 2865, 1633, 1542, 1513, 1214, 1085,954.

EXAMPLE 709N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}pentanamide

Melting point: 190–193° C.

EXAMPLE 710N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopentanecarboxamide

Melting point: 242–244° C. (decomp.)

EXAMPLE 711 N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}benzamide

IR (neat) cm⁻¹; 3297, 3172, 2940, 2865, 1627, 1540, 1083, 950, 694.

EXAMPLE 712 N˜2˜,N˜2˜dimethyl-N˜1˜-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}glycinamide

IR (neat) cm⁻¹; 3286, 2950, 2815, 2765, 1646, 1525, 1513, 1216, 1085,952.

The following compound of Example 713 was synthesized by carrying outreaction according to the method described in Example 399, except forusing the N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}butanamideobtained in Example 708, as a starting material.

EXAMPLE 713 cis-N-butyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 3270, 2937, 2858, 1517, 1209, 939, 792.

The following compound of Example 714 was synthesized by carrying outreaction according to the method described in Example 399, except forusing the N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}pentanamideobtained in Example 709, as a starting material.

EXAMPLE 714cis-3-[(4-Methyl-1H-indazol-5-yl)oxy]-N-pentylcyclohexanamine

IR (neat) cm⁻¹; 3249, 2929, 2863, 2761, 1517, 1220, 1091, 937 cm⁻¹.

The following compound of Example 715 was synthesized by carrying outreaction according to the method described in Example 399, except forusing theN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopentanecarboxamideobtained in Example 710, as a starting material.

EXAMPLE 715cis-N-(cyclopentylmethyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 140–142° C.

The following compound of Example 716 was synthesized by carrying outreaction according to the method described in Example 399, except forusing the N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}benzamideobtained in Example 711, as a starting material.

EXAMPLE 716cis-N-benzyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 3255, 2929, 2854, 1521, 941, 746, 700.

EXAMPLE 717 Synthesis ofcis-N-(2-chlorobenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

To a solution of the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.407 mmol) obtained in Example 411 inmethanol (5 ml) were added 2-chlorobenzaldehyde (46 μl, 0.407 mmol) andacetic acid (23 μl, 0.407 mmol), and the resulting mixture was stirredat room temperature for 30 minutes. Then, acetic acid (46 μl, 0.814mmol) and sodium cyanoborohydride (28 mg, 0.447 mmol) were added theretoand stirred for 2 hours and a half. Subsequently, the reaction solutionwas poured into a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure andthe resulting residue was purified by a silica gel column chromatography(eluent: chloroform/methanol=30/1) to obtaincis-N-(2-chlorobenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine(100 mg, 66%).

¹H-NMR (DMSO-d₆) δ; 0.93–1.02 (1H, m), 1.15–1.31 (3H, m), 1.69–1.73 (1H,m), 1.86–1.89 (1H, m), 1.96–2.00 (1H, m), 2.26–2.30 (1H, m), 2.36 (3H,s), 2.40–2.48 (1H, m), 3.72–3.82 (2H, m), 3.97–4.03 (1H, m), 7.10 (1H,d, J=8.9 Hz), 7.20–7.30 (3H, m), 7.36 (1H, dd, J=7.8, 1.4 Hz), 7.52 (1H,dd, J=7.6, 1.7 Hz), 8.00 (1H, s), 12.86 (1H, s).

The following compounds of Examples 718 to 722 were synthesized bycarrying out reaction according to the method described in Example 717,except for using thecis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example411, as a starting material.

EXAMPLE 718cis-N-(3-chlorobenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 3253, 2931, 2854, 1575, 1213, 941, 786.

EXAMPLE 719cis-N-(4-chlorobenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 0.90–1.00 (1H, m), 1.12–1.31 (3H, m), 1.68–1.71 (1H,m), 1.84–1.87 (1H, m), 1.95–1.99 (1H, m), 2.13 (1H, brs), 2.23–2.26 (1H,m), 2.35–2.42 (4H, m), 3.64–3.72 (2H, m), 3.94–4.00 (1H, m), 7.08 (1H,d, J=8.9 Hz), 7.26 (1H, d, J=8.9 Hz), 7.32 (4H, s), 7.99 (1H, s), 12.86(1H, s).

EXAMPLE 720cis-N-(2-methoxybenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

¹H-NMR (DMSO-d₆) δ; 0.92–1.03 (1H, m), 1.14–1.32 (3H, m), 1.69–1.72 (1H,m), 1.84–1.87 (1H, m), 1.96–1.99 (1H, m), 2.25–2.28 (1H, m), 2.36–2.45(4H, m), 3.62–3.71 (2H, m), 3.72 (3H, s), 3.96–4.01 (1H, m), 6.84–6.91(2H, m), 7.15–7.19 (1H, m), 7.09 (1H, d, J=8.9 Hz), 7.25–7.29 (2H, m),8.00 (1H, s), 12.86 (1H, s).

EXAMPLE 721cis-N-(3-methoxybenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

IR (neat) cm⁻¹; 3261, 2931, 2856, 1612, 1514, 1265, 941, 781.

EXAMPLE 722cis-N-(4-methoxybenzyl)-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 164–166° C.

EXAMPLE 723 Synthesis of4-methyl-5-[(cis-3-piperidin-1-ylcyclohexyl)oxy]-1H-indazole

Under nitrogen, the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine(100 mg, 0.403 mmol) obtained in Example 411 and 25%-glutaraldehyde (187mg, 0.448 mmol) were dissolved in methanol (10 ml), and the resultingsolution was stirred at room temperature for 40 minutes. Then, sodiumcyanoborohydride (51 mg, 0.815 mmol) and acetic acid (0.2 ml) were addedthereto, and the resulting mixture was stirred at room temperature for16 hours. The reaction solution was diluted with chloroform andseparated by the addition of a 1N-aqueous sodium hydroxide solution, andthe desired compound was further extracted from the aqueous layer withchloroform. The combined chloroform layer was washed with water and thena saturated aqueous sodium chloride solution, dried by the addition ofanhydrous magnesium sulfate, and then filtered. The solvent wasdistilled off under reduced pressure and the resulting concentrationresidue was purified by a silica gel column chromatography (eluent:acetonitrile/aqueous ammonia=100/0, 100/2, 100/4) to obtain4-methyl-5-[(cis-3-piperidin-1-ylcyclohexyl)oxy]-1H-indazole (91 mg,yield 71.2%) as a white amorphous substance.

IR (neat) cm⁻¹; 3167, 2933, 2358, 2343, 1508, 1221, 1155, 1095, 985,941.

EXAMPLE 724 Synthesis ofcis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine

Under nitrogen, the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine(500 mg, 2.04 mmol) obtained in Example 411 was suspended indichloromethane (10 ml), and 3,4-dihydro-2H-pyran (205 μl, 2.24 mmol)and pyridinium p-toluenesulfonate (51 mg, 0.204 mmol) were addedthereto, followed by adding thereto p-toluenesulfonic acid monohydrate(387 mg, 2.04 mmol). N-methyl-2-pyrrolidinone (10 ml) was added theretoto effect dissolution, and the resulting solution was stirred asfollows: at room temperature for 17 hours; at 60° C. for 3.5 hours; andthen at 80° C. for 10 hours. The reaction solution was cooled to roomtemperature and a 1N-aqueous sodium hydroxide solution was addedthereto, followed by extraction with chloroform (twice). The combinedchloroform layer was washed with a saturated aqueous sodium chloridesolution, dried by the addition of anhydrous magnesium sulfate, and thenfiltered. The solvent was distilled off under reduced pressure and theresulting concentration residue was purified by a silica gel columnchromatography (eluents: chloroform/methanol=20/1 andchloroform/methanol/aqueous ammonia=10/0.8/0.1) to obtaincis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine(602 mg, yield 89.6%) as colorless tar.

IR (neat) cm⁻¹; 2933, 1504, 1222, 1079, 1039, 980, 912.

EXAMPLE 725 Synthesis of4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole

Under nitrogen, thecis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine(100 mg, 0.304 mmol) obtained in Example 724 was dissolved inN,N-dimethylacetamide (3 ml), followed by adding thereto1,4-dibromobutane (36 μl, 0.304 mmol) and potassium carbonate (105 mg,0.759 mmol), and the resulting mixture was stirred at 80° C. for 1.5hours. The reaction solution was cooled to room temperature and waterwas added thereto, followed by extraction with chloroform (twice). Thecombined chloroform layer was washed with a saturated aqueous sodiumchloride solution, dried by the addition of anhydrous magnesium sulfate,and then filtered. The solvent was distilled off under reduced pressureand the resulting concentration residue was purified by a silica gelcolumn chromatography (eluent: acetonitrile/aqueous ammonia=100/0,100/2) to obtain4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(64 mg, yield 55.0%) as light-yellow tar.

¹H-NMR (CDCl₃) δ; 7.97 (s, 1H), 7.34 (d, 1H, J=9.0 Hz), 7.10 (d, 1H,J=9.0 Hz), 5.66 (dd, 1H, J=9.5, 2.6 Hz), 4.04–3.93 (m, 2H), 2.66 (m,4H), 2.61–2.39 (m, 2H), 2.46 (s, 3H), 2.22–1.98 (m, 5H), 1.86–1.65 (m,8H), 1.54 (m, 1H), 1.48–1.21 (m, 3H).

LC/MS; M+1=384.

EXAMPLE 726 Synthesis of4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazoleMonohydrochloride

Under nitrogen, the4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(60 mg, 0.156 mmol) obtained in Example 725 was dissolved in isopropylalcohol (2 ml), followed by adding thereto a 4N-hydrochloricacid/1,4-dioxane solution (2 ml), and the resulting mixture was stirredat room temperature for 3 hours. The solvent was distilled off underreduced pressure and the resulting concentration residue was purified bya silica gel column chromatography (eluent: acetonitrile/aqueousammonia=100/0, 100/2, 100/4). Then, a 4N-hydrochloric acid/1,4-dioxanesolution was added thereto and the solvent was distilled off underreduced pressure to obtain4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazolemonohydrochloride (55 mg, yield 100%) as a hygroscopic light-yellowsolid.

IR (neat) cm⁻¹; 3600–2300, 1635, 1508, 1456, 1380, 1221, 1089, 997, 943.

EXAMPLE 727 Synthesis of4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole

Under nitrogen, thecis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine(90 mg, 0.273 mmol) obtained in Example 724 was dissolved inN,N-dimethylacetamide (2 ml), followed by adding theretobis(2-bromoethyl) ether (34 μl, 0.273 mmol) and potassium carbonate (94mg, 0.683 mmol), and the resulting mixture was stirred at 80° C. for 6hours. The reaction solution was cooled to room temperature and a1N-aqueous sodium hydroxide solution was added thereto, followed byextraction with chloroform (three times). The combined chloroform layerwas washed with a saturated aqueous sodium chloride solution, dried bythe addition of anhydrous magnesium sulfate, and then filtered. Thesolvent was distilled off under reduced pressure and the resultingconcentration residue was purified by a silica gel column chromatography(eluent: acetonitrile/aqueous ammonia=100/0, 100/1) to obtain4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(83 mg, yield 76.0%) as light-yellow tar.

¹H-NMR (CDCl₃) δ; 7.97 (s, 1H), 7.34 (d, 1H, J=8.8 Hz), 7.10 (d, 1H,J=8.8 Hz), 5.66 (dd, 1H, J=9.4, 2.6 Hz), 4.04–3.93 (m, 2H), 3.71 (m,5H), 2.55 (m, 5H), 2.46 (s, 3H), 2.35 (m, 2H), 2.17–2.01 (m, 3H),1.89–1.65 (m, 5H), 1.49–1.30 (m, 2H), 1.21 (m, 2H).

LC/MS; M+1=400.

EXAMPLE 728 Synthesis of4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1H-indazole

Under nitrogen, the4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(80 mg, 0.200 mmol) obtained in Example 727 was dissolved in isopropylalcohol (3 ml), followed by adding thereto 4N-hydrochloricacid/1,4-dioxane (3 ml), and the resulting mixture was stirred at roomtemperature for 19 hours. The solvent was distilled off under reducedpressure and the resulting concentration residue was purified by asilica gel column chromatography (eluent: acetonitrile/aqueousammonia=100/0, 100/1, 100/2) to obtain4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1H-indazole (55 mg,yield 87.1%) as a white amorphous substance.

IR (neat) cm⁻¹; 3197, 2935, 2858, 1508, 1223, 1113, 1031, 993, 941.

EXAMPLE 729 Synthesis ofN-benzyl-N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine

Under nitrogen, theN-benzyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine (150mg, 0.447 mmol) obtained in Example 716 and 36%-formaldehyde (56 mg,0.671 mmol) were suspended in methanol (5 ml), followed by addingthereto acetic acid (0.2 ml), and the resulting mixture was stirred atroom temperature for 30 minutes. Then, sodium cyanoborohydride (56 mg,0.894 mmol) was added thereto and the resulting mixture was stirred atroom temperature for 17 hours. The reaction mixture was diluted withchloroform and then separated by the addition of a 1N-aqueous sodiumhydroxide solution, and the desired compound was further extracted fromthe aqueous layer with chloroform. The combined chloroform layer waswashed with a saturated aqueous sodium chloride solution, dried by theaddition of anhydrous magnesium sulfate, and then filtered. The solventwas distilled off under reduced pressure and the resulting concentrationresidue was purified by a silica gel column chromatography (eluent:acetonitrile/aqueous ammonia=100/0, 100/1) to obtainN-benzyl-N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine(136 mg, yield 87.0%) as a white amorphous substance.

IR (neat) cm⁻¹; 3172, 2935, 2858, 1508, 1221, 1093, 1001, 941.

EXAMPLE 730 Synthesis ofN-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine

Under nitrogen, theN-benzyl-N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine(80 mg, 0.229 mmol) obtained in Example 729 was dissolved in ethanol (4ml), followed by adding thereto ammonium formate (144 mg, 2.29 mmol) andthen 10%-Pd/C (containing 50% water) (20 mg), and the resulting mixturewas stirred with heating under reflux for 2 hours. The reaction mixturewas cooled to room temperature and the Pd/C was filtered off. Then, thesolvent was distilled off under reduced pressure and the resultingconcentration residue was purified by a silica gel column chromatography(eluent: acetonitrile/aqueous ammonia=100/0, 100/1, 100/2, 100/4) toobtain N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine(50 mg, yield 84.2%) as a white amorphous substance.

IR (neat) cm⁻¹; 3500–1495, 1373, 1218, 1203, 1093, 1025, 943.

EXAMPLE 731 Synthesis ofN-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylaminemonohydrochloride (a) Synthesis ofN-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamineandN-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine

Under nitrogen, tris(dibenzylideneacetone)(chloroform)dipalladium(0) (57mg, 0.0554 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (69mg, 0.111 mmol) were dissolved in toluene (2 ml), and the resultingsolution was stirred at room temperature for 1 hour. A solution preparedby dissolving bromobenzene (117 μl, 1.108 mmol) and thecis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine(365 mg, 1.108 mmol) obtained in Example 724 in toluene (8 ml), andsodium tert-butoxide (213 mg, 2.22 mmol) were added thereto, and theresulting mixture was stirred at 80° C. for 4 hours. The reactionsolution was cooled to room temperature and water was added thereto,followed by extraction with ethyl acetate. The ethyl acetate layer waswashed with water and then a saturated aqueous sodium chloride solution,dried by the addition of anhydrous magnesium sulfate, and then filtered.The solvent was distilled off under reduced pressure and the resultingconcentration residue was purified by a silica gel column chromatography(eluent: n-hexane/ethyl acetate=5/1, 4/1) to obtainN-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine(174 mg, yield 38.7%) as a yellow amorphous substance andN-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine(83 mg, yield 15.6%) as a white amorphous substance.

(b) Synthesis ofN-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylaminemonohydrochloride

Under nitrogen,N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine(100 mg, 0.247 mmol) was dissolved in isopropyl alcohol (4 ml), followedby adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (4 ml),and the resulting mixture was stirred at room temperature for 20 hours.The solvent was distilled off under reduced pressure and the resultingconcentration residue was thoroughly dispersed and suspended inisopropyl alcohol. Thereafter, the solid was collected by filtration,washed with a small volume of isopropyl alcohol and then dried underreduced pressure to obtainN-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine (71mg, yield 80.5%) as a whitely yellow solid.

IR (neat) cm⁻¹; 3100–2300, 1531, 1492, 1388, 1375, 1268, 1213, 1200,978.

EXAMPLE 732 Synthesis ofN-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine

Under nitrogen, theN-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine(82 mg, 0.172 mmol) obtained in Example 731, (a) was dissolved inisopropyl alcohol (4 ml), followed by adding thereto a 4N-hydrochloricacid/1,4-dioxane solution (4 ml), and the resulting mixture was stirredat room temperature for 20 hours. The solvent was distilled off underreduced pressure and a saturated aqueous sodium hydrogencarbonatesolution was added to the residue, followed by extraction with ethylacetate. The ethyl acetate layer was washed with water and then asaturated aqueous sodium chloride solution, dried by the addition ofanhydrous magnesium sulfate, and then filtered. The solvent wasdistilled off under reduced pressure and the resulting concentrationresidue was purified by a silica gel column chromatography (eluent:n-hexane/ethyl acetate=3/1) to obtainN-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine(52 mg, yield 76.8%) as a whitely yellow amorphous substance.

IR (neat) cm⁻¹; 3172, 2937, 2358, 2343, 1587, 1492, 1294, 1223, 1093,1010, 945.

EXAMPLE 733 Synthesis ofN-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine(a) Synthesis ofN-methyl-N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine

Under nitrogen, theN-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine(100 mg, 0.247 mmol) obtained in Example 731, (a) and 36%-formaldehyde(31 mg, 0.370 mmol) were dissolved in methanol (4 ml), followed byadding thereto acetic acid (0.2 ml), and the resulting mixture wasstirred at room temperature for 1 hour. Then, sodium cyanoborohydride(31 mg, 0.493 mmol) was added thereto and the resulting mixture wasstirred at room temperature for 1 hour. The reaction solution wasdiluted with chloroform and separated by the addition of a 1N-aqueoussodium hydroxide solution, and the aqueous layer was further extractedwith chloroform. The combined chloroform layer was washed with asaturated aqueous sodium chloride solution, dried by the addition ofanhydrous magnesium sulfate, and then filtered. The solvent wasdistilled off under reduced pressure and the resulting concentrationresidue was purified by a silica gel column chromatography (eluent:n-hexane/ethyl acetate=5/1) to obtainN-methyl-N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine(89 mg, yield 86.0%) as colorless tar.

(b) Synthesis ofN-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine

Under nitrogen,N-methyl-N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine(89 mg, 0.212 mmol) was dissolved in isopropyl alcohol (4 ml), followedby adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (4 ml),and the resulting mixture was stirred at room temperature for 22 hours.The solvent was distilled off under reduced pressure, and the residuewas neutralized with aqueous ammonia and concentrated to dryness underreduced pressure. The resulting concentration residue was purified by asilica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) toobtainN-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine(62 mg, yield 87.1%) as a white amorphous substance.

IR (neat) cm⁻¹; 3172, 2937, 2859, 1594, 1504, 1223, 1200, 1093, 943.

EXAMPLE 734 Synthesis of 4-methyl-5-(4-nitrophenoxy)-1H-indazole (a)Synthesis of 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol

Under nitrogen, the 4-methyl-1H-indazol-5-ol (500 mg, 3.37 mmol)obtained in Example 402 was suspended in dichloromethane (20 ml),followed by adding thereto 3,4-dihydro-2H-pyran (239 μl, 3.71 mmol) andp-toluenesulfonic acid monohydrate (64 mg, 0.337 mmol). Tetrahydrofuran(25 ml) was added thereto to effect dissolution, and the reaction wascarried out at room temperature for 2 days. The solvent was distilledoff under reduced pressure and water was added to the residue, followedby extraction with ethyl acetate. The ethyl acetate layer was washedwith a saturated aqueous sodium chloride solution, dried by the additionof anhydrous magnesium sulfate, and then filtered. The solvent wasdistilled off under reduced pressure and the resulting concentrationresidue was purified by a silica gel column chromatography (eluent:n-hexane/ethyl acetate=3/1) to obtain4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (477 mg, yield60.9%).

(b) Synthesis of 4-methyl-5-(4-nitrophenoxy)-1H-indazole

Under nitrogen, 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (200mg, 0.861 mmol) was dissolved in N,N-dimethylformamide (5 ml), followedby adding thereto 4-fluoronitrobenzene (100 μl, 0.947 mmol) andpotassium carbonate (179 mg, 1.29 mmol), and the resulting mixture wasstirred at 50° C. for 1 hour. After the reaction solution was cooled toroom temperature, a 1N-aqueous hydrochloric acid solution (6 ml) andmethanol (3 ml) were added thereto and the resulting mixture was stirredat room temperature for 2 hours. The mixture was adjusted to pH 9 with asaturated aqueous sodium hydrogencarbonate solution and extracted twicewith ethyl acetate/toluene=3/1. The combined extract layer was washedwith water and then a saturated aqueous sodium chloride solution, driedby the addition of anhydrous magnesium sulfate, and then filtered. Thesolvent was distilled off under reduced pressure and the resultingconcentration residue was purified by a silica gel column chromatography(eluent: n-hexane/ethyl acetate=3/1) to obtain4-methyl-5-(4-nitrophenoxy)-1H-indazole (192 mg, yield 82.8%) as ayellow solid.

IR (neat) cm⁻¹; 3180, 2359, 2343, 1589, 1506, 1487, 1348, 1348, 1111.

EXAMPLE 735 Synthesis of 4-[(4-methyl-1H-indazol-5-yl)oxy]anilinemonohydrochloride

Under nitrogen, the 4-methyl-5-(4-nitrophenoxy)-1H-indazole (139 mg,0.516 mmol) obtained in Example 734 was dissolved in methanol (20 ml),followed by adding thereto 10%-Pd/C (containing 50% water) (20 mg), andthe resulting mixture was stirred under a hydrogen atmosphere for 1.5hours at ordinary temperature and atmospheric pressure. After thereplacement on the nitrogen, the Pd/C was filtered off and then thesolvent was distilled off under reduced pressure. A portion (50 mg,0.186 mmol) of the resulting concentration residue was dissolved inisopropyl alcohol (3 ml), followed by adding thereto a 4N-hydrochloricacid/1,4-dioxane solution (2 ml), and the resulting mixture was stirredat room temperature for 1.5 hours. The solid precipitated was collectedby filtration, washed with the filtrate and then a small volume ofisopropyl alcohol, and dried under reduced pressure to obtain4-[(4-methyl-1H-indazol-5-yl)oxy]aniline monohydrochloride (39 mg, yield78%) as a white solid.

IR (neat) cm⁻¹; 3200–2200, 1504, 1241, 1201, 1103.

EXAMPLE 736 Synthesis of 4-methyl-5-(3-nitrophenoxy)-1H-indazole (a)Synthesis of4-methyl-5-(3-nitrophenoxy)-1-tetrahydro-2H-pyran-2-yl-1H-indazole

Under nitrogen, the 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol(130 mg, 0.560 mmol) obtained in Example 734, (a) and m-dinitrobenzene(103 mg, 0.615 mmol) were dissolved in N-methyl-2-pyrrolidinone (4 ml),followed by adding thereto potassium carbonate (193 mg, 1.39 mmol), andthe resulting mixture was stirred at 120° C. for 2 hours and then at150° C. for 2 hours. Water was added to the reaction solution, followedby extraction with toluene/ethyl acetate=1/3 (twice). The combinedextract layer was washed with water and then a saturated aqueous sodiumchloride solution, dried by the addition of anhydrous magnesium sulfate,and then filtered. The solvent was distilled off under reduced pressureand the resulting concentration residue was purified by a silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=5/1) to obtain4-methyl-5-(3-nitrophenoxy)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (136mg, yield 69%) as a yellow solid.

(b) Synthesis of 4-methyl-5-(3-nitrophenoxy)-1H-indazole

Under nitrogen,4-methyl-S-(3-nitrophenoxy)-1-tetrahydro-2H-pyran-2-yl-1H-indazole (136mg, 0.385 mmol) was dissolved in methanol (5 ml), followed by addingthereto a 4N-hydrochloric acid/1,4-dioxane solution (5 ml), and theresulting mixture was stirred at room temperature for 2 hours. After thesolvent was distilled off under reduced pressure, a saturated aqueoussodium hydrogencarbonate solution was added to the residue, followed byextraction with ethyl acetate. The ethyl acetate layer was washed withwater and then a saturated aqueous sodium chloride solution, dried bythe addition of anhydrous magnesium sulfate, and then filtered. Thesolvent was distilled off under reduced pressure and the resultingconcentration residue was purified by a silica gel column chromatography(eluent: n-hexane/ethyl acetate=3/1) to obtain4-methyl-5-(3-nitrophenoxy)-1H-indazole (94 mg, yield 91%).

IR (neat) cm⁻¹; 3500–2700, 1531, 1513, 1473, 1346, 1276, 1232, 939.

EXAMPLE 737 Synthesis of 3-[(4-methyl-1H-indazol-5-yl)oxy]anilinemonohydrochloride

Under nitrogen, the 4-methyl-5-(3-nitrophenoxy)-1H-indazole (60 mg,0.223 mmol) obtained in Example 736 was dissolved in methanol (10 ml),followed by adding thereto 10%-Pd/C (containing water) (20 mg), and theresulting mixture was stirred at room temperature for 2 hours whileadding hydrogen thereto. After the replacement on the nitrogen(theoretical amount of hydrogen: 15 ml), the Pd/C was filtered off bythe use of Celite and then the solvent was distilled off under reducedpressure. The resulting concentration residue was dissolved in isopropylalcohol (1 ml), followed by adding thereto a 4N-hydrochloricacid/1,4-dioxane solution (2 ml), and the resulting mixture was stirredat room temperature for 1 hour and then under ice-cooling for 1 hour.The white solid precipitated was collected by filtration, washed withdiethyl ether, and dried under reduced pressure to obtain3-[(4-methyl-1H-indazol-5-yl)oxy]aniline monohydrochloride (50 mg, yield81%) as a white solid.

IR (neat) cm⁻¹; 3300–2200, 1531, 1485, 1387, 1270, 1254, 1203, 1141,1082, 953.

EXAMPLE 738 Synthesis of5-(2-chloro-4-nitrophenoxy)-4-methyl-1H-indazole

Under nitrogen, the 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol(150 mg, 0.646 mmol) obtained in Example 734, (a) and3-chloro-4-fluoronitrobenzene (125 mg, 0.710 mmol) were dissolved inN,N-dimethylformamide (2 ml), followed by adding thereto potassiumcarbonate (134 mg, 0.969 mmol), and the resulting mixture was stirred at70° C. for 1.5 hours. After the reaction solution was cooled to roomtemperature, water was added thereto, followed by extraction withtoluene/ethyl acetate=1/3. The extract layer was washed with water andthen a saturated aqueous sodium chloride solution, dried by the additionof anhydrous magnesium sulfate, and then filtered. The solvent wasdistilled off under reduced pressure and the resulting concentrationresidue was suspended in methanol (10 ml), followed by adding thereto a4N-hydrochloric acid/1,4-dioxane solution (5 ml), and the resultingmixture was stirred at room temperature for 14 hours. (The residue wasonce dissolved and then gave a white suspension again). The resultingmixture was made basic by adding triethylamine slowly under ice-cooling,and the solvent was distilled off under reduced pressure. Then, waterwas added to the residue, followed by extraction with ethyl acetate. Theextract layer was washed with a saturated aqueous sodium chloridesolution, dried by the addition of anhydrous magnesium sulfate, and thenfiltered. The solvent was distilled off under reduced pressure and theresulting concentration residue was purified by a silica gel columnchromatography (eluent: n-hexane/ethyl acetate=3/1, 2/1) to obtain5-(2-chloro-4-nitrophenoxy)-4-methyl-1H-indazole (168 mg, yield 86%).

IR (neat) cm⁻¹; 3313, 1583, 1516, 1471, 1338, 1265, 1209, 1120, 1080,1055, 906, 895.

EXAMPLE 739 Synthesis of3-chloro-4-[(4-methyl-1H-indazol-5-yl)oxy]aniline monohydrochloride

Under nitrogen, the 5-(2-chloro-4-nitrophenoxy)-4-methyl-1H-indazole(120 mg, 0.395 mmol) obtained in Example 738 was dissolved in ethanol (6ml), followed by adding thereto tin(II) chloride dihydrate (446 mg, 1.98mmol), and the resulting mixture was stirred at 80° C. for 1 hour. Thereaction solution was cooled to room temperature and then poured intowater, and the resulting mixture was adjusted to pH>8 with a 1N aqueoussodium hydroxide solution and extracted twice with ethylacetate/tetrahydrofuran=5/1. The combined extract layer was washed withwater and then a saturated aqueous sodium chloride solution, dried bythe addition of anhydrous magnesium sulfate, and then filtered. Thesolvent was distilled off under reduced pressure and the resultingconcentration residue was purified by a silica gel column chromatography(eluent: n-hexane/ethyl acetate=2/1, 1/1, 1/2) to obtain a yellow solid.The solid obtained was dissolved in 1,4-dioxane (2 ml), followed byadding thereto a 4N-hydrochloric acid/1,4-dioxane solution (2 ml), andthe resulting mixture was stirred at room temperature. Thereafter,diethyl ether (about 15 ml) was added thereto and stirred, and theyellow solid precipitated was collected by filtration, washed withdiethyl ether and then dried under reduced pressure to obtain3-chloro-4-[(4-methyl-1H-indazol-5-yl)oxy]aniline monohydrochloride (45mg, yield 42%).

IR (neat) cm⁻¹; 3300–2150, 1489, 1389, 1255, 1205, 1061, 806.

EXAMPLE 740 Synthesis of 3-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrileMonohydrochloride (a) Synthesis of3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile

Under nitrogen, the 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol(300 mg, 1.29 mmol) obtained in Example 734, (a) and 3-nitrobenzonitrile(210 mg, 1.42 mmol) were dissolved in N-methyl-2-pyrrolidinone (6 ml),followed by adding thereto potassium carbonate (446 mg, 3.23 mmol), andthe resulting mixture was stirred at 150° C. for 16 hours. After thereaction solution was cooled to room temperature, water was addedthereto and the resulting mixture was adjusted to pH 6 with a 1N-aqueoushydrochloric acid solution and extracted with toluene/ethyl acetate=1/3.The extract layer was washed with water and then a saturated aqueoussodium chloride solution, dried by the addition of anhydrous magnesiumsulfate, and then filtered. The solvent was distilled off under reducedpressure and the resulting concentration residue was purified by asilica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1,3/1, 2/1) to obtain3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile(299 mg, yield 69%).

(b) Synthesis of 3-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrileMonohydrochloride

Under nitrogen,3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile(299 mg, 0.897 mmol) was dissolved in a mixture of isopropyl alcohol (6ml) and 1,4-dioxane (6 ml), followed by adding thereto a 4N-hydrochloricacid/1,4-dioxane solution (6 ml), and the resulting mixture was stirredat room temperature for 23 hours. After diethyl ether (30 ml) was addedthereto and stirred, the precipitate was collected by filtration, washedwith diethyl ether and then dried under reduced pressure to obtain3-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrile hydrochloride (176 mg,yield 69%).

IR (neat) cm⁻¹; 3100–2050, 1581, 1529, 1479, 1429, 1388, 1246, 1157,939.

EXAMPLE 741 Synthesis of 4-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrileMonohydrochloride (a) Synthesis of4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile

Under nitrogen, the 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol(300 mg, 1.29 mmol) obtained in Example 734, (a) and4-fluorobenzonitrile (172 mg, 1.42 mmol) were dissolved inN,N-dimethylformamide (6 ml), followed by adding thereto potassiumcarbonate (268 mg, 1.94 mmol), and the resulting mixture was stirred at50° C. for 2 hours and then at 70° C. for 22 hours. After the reactionsolution was cooled to room temperature, water was added thereto,followed by extraction with toluene/ethyl acetate=1/2 (twice). Thecombined extract layer was washed with water and then a saturatedaqueous sodium chloride solution, dried by the addition of anhydrousmagnesium sulfate, and then filtered. The solvent was distilled offunder reduced pressure and the resulting concentration residue waspurified by a silica gel column chromatography (eluent: n-hexane/ethylacetate=5/1, 4/1) to obtain4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile(342 mg, yield 79%).

(b) Synthesis of 4-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrilemonohydrochloride

Under nitrogen,4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile(338 mg, 1.01 mmol) was dissolved in 1,4-dioxane (6 ml), followed byadding thereto a 4N-hydrochloric acid/1,4-dioxane solution (6 ml), andthe resulting mixture was stirred at room temperature for 23 hours.After diethyl ether (30 ml) was added thereto and stirred, theprecipitate was collected by filtration, washed with diethyl ether andthen dried under reduced pressure to obtain4-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrile monohydrochloride (239 mg,yield 83%).

IR (neat) cm⁻¹; 3100–2040, 1604, 1527, 1500, 1388, 1261, 1238, 1167,1155.

EXAMPLE 742 Synthesis of1-[4-[(4-methyl-1H-indazol-5-yl)oxy]phenyl]methylamine monohydrochloride

Under nitrogen, the 4-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrilemonohydrochloride (70 mg, 0.245 mmol) obtained in Example 741 wassuspended in tetrahydrofuran (2 ml), and lithium aluminum hydride (46mg, 1.22 mmol) was added thereto under ice-cooling. The resultingmixture was cooled to room temperature and stirred for 4 hours. Underice-cooling, water (46 μl) was slowly added thereto, followed by addingthereto a 4N-aqueous sodium hydroxide solution (46 μl), water (140 μl)and tetrahydrofuran (5 ml), and the resulting mixture was stirred atroom temperature. The precipitate was filtered off, and the residue waswashed with tetrahydrofuran and then distilled under reduced pressure toremove the solvent. The resulting concentration residue was purified bya silica gel column chromatography (eluent: acetonitrile/aqueousammonia=100/0, 50/1, 25/1) to obtain a white solid (41 mg). The solidobtained was dissolved in 1,4-dioxane (2 ml), followed by adding theretoa 4N-hydrochloric acid/1,4-dioxane solution (2 ml), and the resultingmixture was stirred at room temperature for 1 hour. Then, diethyl ether(about 15 ml) was added thereto and stirred, and the resulting whitesolid was collected by filtration, washed with diethyl ether and thendried under reduced pressure to obtain1-[4-[(4-methyl-1H-indazol-5-yl)oxy]phenyl]methylamine monohydrochloride(46 mg, yield 65%).

IR (neat) cm⁻¹; 3060–2060, 1508, 1230, 835.

EXAMPLE 743 Synthesis of1-[3-[(4-methyl-1H-indazol-5-yl)oxy]phenyl]methylamine monohydrochloride

Under nitrogen, the 3-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrilemonohydrochloride (60 mg, 0.210 mmol) obtained in Example 740 wassuspended in tetrahydrofuran (2 ml), and lithium aluminum hydride (40mg, 1.05 mmol) was added thereto under ice-cooling. The resultingmixture was cooled to room temperature and stirred for 4 hours. Underice-cooling, water (40 μl) was slowly added thereto, followed by addingthereto a 4N-aqueous sodium hydroxide solution (40 μl), water (120 μl)and tetrahydrofuran (5 ml), and the resulting mixture was stirred atroom temperature. The precipitate was filtered off, and the residue waswashed with tetrahydrofuran and then distilled under reduced pressure toremove the solvent. The resulting concentration residue was purified bya silica gel column chromatography (eluent: acetonitrile/aqueousammonia=100/0, 50/1, 25/1) to obtain a white solid (31 mg). The solidobtained was dissolved in 1,4-dioxane (2 ml), followed by adding theretoa 4N-hydrochloric acid/1,4-dioxane solution (2 ml), and the resultingmixture was stirred at room temperature for 1 hour. Then, diethyl ether(about 15 ml) was added thereto and stirred, and the resulting whitesolid was collected by filtration, washed with diethyl ether and thendried under reduced pressure to obtain1-[3-[(4-methyl-1H-indazol-5-yl)oxy]phenyl]methylamine monohydrochloride(39 mg, yield 64%).

IR (neat) cm⁻¹; 3200–2100, 1589, 1527, 1489, 1446, 1385, 1251, 1207,1161, 1101, 937.

EXAMPLE 744 Synthesis oftrans-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine (a) Synthesis oftrans-2-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione

A cyanomethylenetributylphosphorane/toluene solution (1.2 g, 4.53 mmol)was added to a solution prepared by dissolving the4-ethyl-1H-indazol-5-ol (359 mg, 1.46 mmol) obtained in Example 682 andthe cis-2-(4-hydroxycyclohexyl)-1H-isoinzole-1,3(2H)-dione (854 mg, 3.48mmol) obtained in Example 323, (c) in toluene (15 ml), and the resultingmixture was stirred at 120° C. for 3 hours. The reaction solution wasconcentrated, and to the resulting residue were added chloroform and a1N-aqueous sodium hydroxide solution to effect partition, followed byextraction with chloroform (twice). The extract solution was dried overanhydrous magnesium sulfate. The residue was purified by a silica gelchromatography (hexane/ethyl acetate=2/1) to obtaintrans-2-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(681.1 mg, 50%).

(b) 4-((4-Ethyl-1H-indazol-5-yl)oxy)cyclohexanamine hydrochloride wasobtained by carrying out reaction according to the method described inExample 14, except for usingtrans-2-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione.

IR (neat) cm⁻¹; 800, 1072, 1122, 1257, 1508.

EXAMPLE 745 Synthesis ofcis-3-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine

cis-3-((4-Ethyl-1H-indazol-5-yl)oxy)cyclohexanamine was obtained bycarrying out reaction according to the method described in Example 744,except for using thetrans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 385, (b).

LC/MS: M+1=288.0

EXAMPLE 746 Synthesis ofcis-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine

cis-4-((4-Ethyl-1H-indazol-5-yl)oxy)cyclohexanamine was obtained bycarrying out reaction according to the method described in Example 744,except for using thetrans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 323, (a).

LC/MS: M+1=260.3

EXAMPLE 747 Synthesis oftrans-3-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine

trans-3-((4-Ethyl-1H-indazol-5-yl)oxy)cyclo-hexanamine was obtained bycarrying out reaction according to the method described in Example 744,except for using thecis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained inExample 326, (d).

IR (neat) cm⁻¹; 906, 945, 1107, 1223, 1506.

The following compounds of Examples 748 and 749 were synthesized bycarrying out reaction according to the method described in Example 389,except for using thetrans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained inExample 409, as a starting material.

EXAMPLE 748trans-N,N-dimethyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

IR (neat) cm⁻¹; 2643, 1220, 1151, 964.

EXAMPLE 749trans-N,N-dipropyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

LC/MS: M+1=330

The following compound of Example 750 was synthesized by carrying outreaction according to the method described in Example 140, except forusing the trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 409, as a starting material.

EXAMPLE 750trans-N-cyclopentyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

Melting point: 110–112° C.

EXAMPLE 751 Synthesis oftrans-N-ethyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (a)Synthesis ofN-{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

The title compound was synthesized by carrying out reaction according tothe method described in Example 391, except for using thetrans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained inExample 409, as a starting material.

(b) Synthesis oftrans-N-ethyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine

The title compound was synthesized by carrying out reaction according tothe method described in Example 399, except for usingN-{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide as astarting material.

Melting point: 95–97° C.

EXAMPLE 752 Synthesis oftrans-N-propyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride (a) Synthesis ofN-{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

The title compound was synthesized by carrying out reaction according tothe method described in Example 391, except for using thetrans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained inExample 409, as a starting material.

(b) Synthesis oftrans-N-propyl-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

The title compound was synthesized by carrying out reaction according tothe method described in Example 392, except for usingN-{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide as astarting material.

IR (neat) cm⁻¹; 2782, 1222, 1091, 970, 941.

EXAMPLE 753 Synthesis ofN,N-dimethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Acetic acid (0.060 ml) was added to a methanolic solution (1.0 ml) ofthe cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (46 mg, 0.20mmol) obtained in Example 411, followed by adding theretoparaformaldehyde (30 mg, 1.0 mmol), and the resulting mixture wasstirred at room temperature for 2 hours. Then, a methanolic solution(0.5 ml) of sodium cyanoborohydride (63 mg, 1.0 mmol) was added theretoand the resulting mixture was stirred overnight at room temperature. A1N-aqueous sodium hydroxide solution (0.8 ml) was added to the reactionsolution and the solvent was distilled off. The residue oil was purifiedby elution by a silica gel column chromatography (hexane/ethylacetate/triethylamine=5:15:1) to obtainN,N-dimethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine(29.8 mg, 54%).

MS: m/z=274 (M+1)

The following compounds of Examples 754 to 757 were synthesized bycarrying out reaction according to the method described in Example 753.

EXAMPLE 754N,N-dipropyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

MS: m/z=330 (M+1)

EXAMPLE 755N,N-dibutyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

MS: m/z=358 (M+1)

EXAMPLE 756N-isopropyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Melting point: 152–156° C.

EXAMPLE 757N-cyclopentyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Melting point: 166–168° C.

EXAMPLE 758 Synthesis ofN-ethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (a)Synthesis of N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylacetamide

Acetic acid (0.036 g, 0.60 mmol), triethylamine (0.21 ml, 1.5 mmol),1-hydroxybenztriazole (0.081 g, 0.60 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.115g, 0.60 mmol) were added to a solution of thecis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (147 mg, 0.60 mmol)obtained in Example 411 in N,N-dimethylformamide (2 ml) and stirredovernight. A 2N-aqueous lithium hydroxide solution (2 ml) was addedthereto, and the resulting mixture was stirred for some time, added towater, and then extracted three times with toluene/ethyl acetate=1/1.The organic layer was washed with water and a saturated aqueous sodiumchloride solution and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the solid precipitated wassuspended in a hexane/ethyl acetate mixed solvent and stirred to bewashed. The solid was collected by filtration and dried under reducedpressure to obtainN-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylacetamide (163 mg,95%).

¹H-NMR (DMSO-d₆) δ; 1.20–1.30 (3H, m), 1.65–1.97 (5H, m), 1.92–2.14 (2H,m), 2.29 (1H, s), 2.37 (3H, s), 3.46–3.63 (1H, m), 3.99–4.10 (1H, m),7.07–7.18 (1H, m), 7.18–7.32 (1H, m), 8.00 (1H, s), 12.87 (1H, s).

(b) Synthesis ofN-ethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylacetamide (0.153 g,0.53 mmol) was added to a suspension of lithium aluminum hydride (0.057g, 1.5 mmol) in tetrahydrofuran (10 ml), and the resulting mixture wasstirred with heating under reflux for 2 hours. The resulting solutionwas cooled on an ice bath, and water (0.02 ml), a 2N-aqueous sodiumhydroxide solution (0.04 ml) and water (0.04 ml) were added dropwisethereto in that order. Then, the insoluble material was removed byfiltration using Celite. The filtrate was purified by elution by asilica gel column chromatography (hexane/ethylacetate/triethylamine=5:15:1) to obtainN-ethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclo-hexylamine (91.5mg, 63%).

MS: m/z=274 (M+1)

The following compound of Example 759 was synthesized by carrying outreaction according to the method described in Example 758.

EXAMPLE 759 EXAMPLE 9N-propyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

MS: m/z=288 (M+1)

EXAMPLE 760 Synthesis ofN,N-diethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (a)Synthesis ofN-ethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylacetamide

Acetic acid (0.013 g, 0.22 mmol), triethylamine (0.070 ml, 0.50 mmol),1-hydroxybenztriazole (0.029 g, 0.22 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.042g, 0.22 mmol) were added to a solution of theN-ethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (59.4 mg,0.217 mmol) obtained in Example 758 in N,N-dimethylformamide (1 ml) andstirred overnight. A 2N-aqueous lithium hydroxide solution (2 ml) wasadded thereto, and the resulting mixture was stirred for some time,added to water, and then extracted three times with toluene/ethylacetate=1/1. The organic layer was washed with water and a saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and thesolid precipitated was suspended in a hexane/ethyl acetate mixed solventand stirred to be washed. The solid was collected by filtration anddried under reduced pressure to obtainN-ethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylacetamide (63.4mg, 93%).

¹H-NMR (DMSO-d₆) δ; 0.92–1.15 (3H, m), 1.15–1.52 (4H, m), 1.52–1.84 (4H,m), 1.84–2.20 (4H, m), 2.29 (1H, s), 2.38 (3H, s), 3.16–3.29 (1H, m),3.96–4.14 (1H, m), 7.07–7.18 (1H, m), 7.18–7.32 (1H, m), 8.00 (1H, s),12.87 (1H, s).

(b) Synthesis ofN,N-diethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

N-ethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylacetamide(0.057 g, 0.18 mmol) was added to a suspension of lithium aluminumhydride (0.020 g, 0.053 mmol) in tetrahydrofuran (5 ml), and theresulting mixture was stirred with heating under reflux for 2 hours. Theresulting solution was cooled on an ice bath, and water (0.04 ml), a2N-aqueous sodium hydroxide solution (0.08 ml) and water (0.12 ml) wereadded dropwise thereto in that order. Then, the insoluble material wasremoved by filtration using Celite. The filtrate was purified by elutionby a silica gel column chromatography (hexane/ethylacetate/triethylamine=5:15:1) to obtainN,N-diethyl-N-cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (29.2mg, 53%).

MS: m/z=302 (M+1)

The following compound of Example 761 was synthesized by carrying outreaction according to the method described in Example 760, except forusing the cis-N-ethyl-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamineobtained in Example 466, as a starting material.

EXAMPLE 761N,N-diethyl-N-cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

MS: m/z=302 (M+1)

EXAMPLE 762 Synthesis oftrans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine (a)Synthesis of2-{trans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione

Diisopropyl dicarboxylate (0.364 g, 1.80 mmol) was added dropwise to amixture of the 5-hydroxy-4-trifluoromethyl-11H-indazole (0.303 g, 1.50mmol) obtained in Example 474, thecis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (0.368 g, 1.50mmol) obtained in Example 326, (d), triphenylphosphine (433 mg, 1.65mmol) and tetrahydrofuran (10 ml) under ice-cooling. After 30 minutes,the mixture thus obtained was warmed up to room temperature and stirredovernight. The reaction mixture was concentrated and then the residueoil was purified by elution by a silica gel column chromatography(hexane/ethyl acetate=3:1 to 2:1) to obtain 0.324 g of a crude product2-{trans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(a mixture with cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione).

(b) Synthesis oftrans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine

A mixture of the crude product2-{trans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(0.324 g) and a 30% methylamine/methanol solution (15 ml) was stirred at90° C. for 3 hours. The solvent was distilled off and the residue solidwas purified by elution by a silica gel column chromatography(chloroform/methanol=20:1→chloroform/methanol/triethylamine=10:1:1) toobtain trans-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine(70.4 mg, 16%, two steps).

NMR (DMSO-d₆) δ; 0.80–1.30 (2H m), 1.35–1.97 (4H, m), 1.90–2.11 (1H, m),2.67–2.80 (1H, m), 2.95–3.10 (1H, m), 3.29–3.41 (1H, m), 4.97 (1H, s),7.40 (2H, d, J=9.2 Hz), 7.81 (1H, d, J=9.0 Hz), 8.01 (1H, s).

EXAMPLE 763 Synthesis ofN-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylacetamide

Acetic acid (0.014 g, 0.22 mmol), triethylamine (0.075 ml, 0.54 mmol),1-hydroxybenztriazole (0.030 g, 0.22 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.043g, 0.22 mmol) were added to a solution of thecis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine (0.066 g,0.22 mmol) obtained in Example 587 in N,N-dimethylformamide (1 ml) andstirred overnight. A 2N-aqueous lithium hydroxide solution (0.4 ml) wasadded thereto, and the resulting mixture was stirred for some time,added to water, and then extracted three times with toluene/ethylacetate=1/1. The organic layer was washed with water and a saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and thesolid precipitated was suspended in a hexane/ethyl acetate mixed solventand stirred to be washed. The solid was collected by filtration anddried under reduced pressure to obtainN-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylacetamide(0.067 g, 89%).

¹H-NMR (DMSO-d₆) δ; 0.93–1.40 (4H, m), 1.65–1.85 (5H, m), 1.94–2.20 (2H,m), 3.52–3.73 (1H, m), 4.45–4.62 (1H, m), 7.47 (1H, d, J=9.1 Hz), 7.80(1H, d, J=9.4 Hz), 8.00 (1H, s), 13.42 (1H, s).

The following compound of Example 764 was synthesized by carrying outreaction according to the method described in Example 763.

EXAMPLE 764N-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylpropanamide

¹H-NMR (DMSO-d₆) δ; 0.94 (1H, d, J=7.6 Hz), 1.02–1.38 (4H, m), 1.67–1.80(2H, m), 1.95–2.15 (4H, m), 3.57–3.75 (1H, m), 4.45–4.60 (1H m), 7.47(1H, d, J=9.1 Hz), 7.80 (1H, d, J=9.4 Hz), 8.00 (1H, s), 13.42 (1H, s).

EXAMPLE 765 Synthesis ofN-ethyl-N-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine

The N-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylacetamide(0.062 g, 0.18 mmol) obtained in Example 16 was added to a suspension oflithium aluminum hydride (0.020 g, 0.54 mmol) in tetrahydrofuran (3 ml),and the resulting mixture was stirred with heating under reflux for 7hours. The resulting solution was cooled on an ice bath, and water (0.02ml), a 2N-aqueous sodium hydroxide solution (0.04 ml) and water (0.08ml) were added dropwise thereto in that order. Then, the insolublematerial was removed by filtration using Celite. The filtrate waspurified by elution by a silica gel column chromatography (ethylacetate/triethylamine=20:1) to obtainN-ethyl-N-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine(27.8 mg, 47%).

Melting point: 158–163° C.

The following compound of Example 766 was synthesized by carrying outreaction according to the method described in Example 765, except forusing theN-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylpropanamideobtained in Example 764, as a starting material.

EXAMPLE 766N-propyl-N-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1504, 1329, 1234, 1119, 1037, 903.

EXAMPLE 767 Synthesis ofN,N-dimethyl-N-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine

Acetic acid (0.065 ml) was added to a methanolic solution (1.0 ml) ofthe cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine (70mg, 0.24 mmol) obtained in Example 587, followed by adding thereto a 37%aqueous formaldehyde solution (35 mg, 1.2 mmol), and the resultingmixture was stirred at room temperature for 2 hours. Then, a methanolicsolution (0.5 ml) of sodium cyanoborohydride (70 mg, 1.1 mmol) was addedthereto and the resulting mixture was stirred overnight at roomtemperature. A 1N-aqueous sodium hydroxide solution (0.8 ml) was addedto the reaction solution and the solvent was distilled off. The residueoil was purified by elution by a silica gel column chromatography (ethylacetate/triethylamine/ethanol=20:1:1) to obtainN,N-dimethyl-N-cis-3-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine(48.3 mg, 63%).

IR (neat) cm⁻¹; 1508, 1329, 1236, 1115, 901.

The following compound of Example 768 was synthesized by carrying outreaction according to the method described in Example 767, except forusing thetrans-4-{[4-(trifluoromethyl)-1H-indazol-5-yl]oxy}cyclohexanamineobtained in Example 586, as a starting material.

EXAMPLE 768N,N-dimethyl-N-trans-4-[(4-trifluoromethyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1506, 1327, 1236, 1188, 1120, 1052, 941, 902.

EXAMPLE 769 Synthesis ofN-benzyl-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Acetic acid (0.060 ml) was added to a methanolic solution (2.0 ml) ofthe trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (98 mg, 0.40mmol) obtained in Example 408, followed by adding thereto benzaldehyde(85 mg, 0.80 mmol), and the resulting mixture was stirred at roomtemperature for 2 hours. Then, a methanolic solution (0.5 ml) of sodiumcyanoborohydride (30 mg, 0.48 mmol) was added thereto and the resultingmixture was stirred overnight at room temperature. A 1N-aqueous sodiumhydroxide solution (0.8 ml) was added to the reaction solution and thesolvent was distilled off. The residue oil was purified by elution by asilica gel column chromatography (hexane/ethyl acetate=1:2→ethylacetate/triethylamine=20:1) to obtainN-benzyl-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (45.6mg, 31%).

IR (neat) cm⁻¹; 1452, 1232, 1099, 935, 804, 744, 696.

The following compounds of Examples 770 to 781 were synthesized bycarrying out reaction according to the method described in Example 769.

EXAMPLE 770N-(2-chlorobenzyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1232, 1101, 943, 800, 754.

EXAMPLE 771N-(3-chlorobenzyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Melting point: 134–137° C.

EXAMPLE 772N-(4-chlorobenzyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Melting point: 148–150° C.

EXAMPLE 773N-(3-methoxybenzyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Melting point: 150–153° C.

EXAMPLE 774N-(4-methoxybenzyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Melting point: 176–178° C.

EXAMPLE 775N-(3-trifluoromethylbenzyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1508, 1327, 1120, 943, 804, 702.

EXAMPLE 776N-(1,3-benzodioxol-5-ylmethyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1247, 1034, 928, 796.

EXAMPLE 777N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl-N-(pyridin-2-ylmethyl)amine

IR (neat) cm⁻¹; 1508, 1221, 1091, 941, 756.

EXAMPLE 778N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl-N-(pyridin-3-ylmethyl)amine

IR (neat) cm⁻¹; 1508, 1222, 1091, 941, 755.

EXAMPLE 779N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl-N-(pyridin-4-ylmethyl)amine

IR (neat) cm⁻¹; 1558, 1222, 1095, 941, 796.

EXAMPLE 780N-isobutyl-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1236, 1101, 935, 873, 790.

EXAMPLE 781N-phenethyl-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1508, 1220, 1093, 940.

EXAMPLE 782 Synthesis ofN-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopropanecarboxamide

Cyclopropanecarboxylic acid (0.034 g, 0.40 mmol), triethylamine (0.14ml, 1.0 mmol), 1-hydroxybenztriazole (0.054 g, 0.40 mmol) and1-ethyl-3-(3′-dimethylamino-propyl)carbodiimide monohydrochloride (0.077g, 0.40 mmol) were added to a solution of thetrans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine (98 mg, 0.40mmol) obtained in Example 408 in N,N-dimethylformamide (2 ml) andstirred overnight. A 2N-aqueous lithium hydroxide solution (2 ml) wasadded thereto, and the resulting mixture was stirred for a while, thenadded to water, and extracted three times with toluene/ethylacetate=1/1. The organic layer was washed with water and a saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and thesolid precipitated was suspended in a hexane/ethyl acetate mixed solventand stirred to be washed. The solid was collected by filtration anddried under reduced pressure to obtainN-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopropanecarboxamide(115 mg, 92%).

¹H-NMR (DMSO-d₆) δ; 0.55–0.67 (4H, m), 1.15–1.32 (2H, m), 1.38–1.53 (3H,m), 1.75–1.86 (2H, m), 1.95–2.06 (2H m), 2.36 (3H, s), 3.50–3.65 (1H,m), 3.97–4.09 (1H m), 7.12 (1H, d, J=9.0 Hz), 7.27 (1H, d, J=9.0 Hz),8.00 (1H, s), 12.84 (1H, s).

The following compounds of Examples 783 to 787 were synthesized bycarrying out reaction according to the method described in Example 782.

EXAMPLE 783N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopentanecarboxamide

¹H-NMR (DMSO-d₆) δ; 1.13–1.30 (2H, m), 1.36–1.73 (11H, m), 1.74–1.85(2H, m), 1.95–2.06 (2H, m), 2.36 (3H, s), 3.46–3.65 (1H, m), 3.95–4.07(1H, m), 7.12 (1H, d, J=9.0 Hz), 7.27 (1H, d, J=9.0 Hz), 7.61 (1H, d,J=7.7 Hz), 8.00 (1H, s), 12.85 (1H, s).

EXAMPLE 7842-Methoxy-N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

¹H-NMR (DMSO-d₆) δ; 1.26–1.53 (4H, m), 1.70–1.81 (2H, m), 1.90–2.06 (2H,m), 2.37 (3H, s), 3.27 (3H, s), 3.58–3.70 (1H, m), 3.75 (2H, s),3.95–4.03 (1H, m), 7.11 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=8.6 Hz), 7.56(1H, d, J=8.0 Hz), 8.00 (1H, s), 12.86 (1H, s).

EXAMPLE 785N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofurane-2-carboxamide

¹H-NMR (DMSO-d₆) δ; 1.17–1.55 (4H, m), 1.69–1.86 (5H, m), 1.96–2.16 (3H,m), 2.37 (3H, s), 3.52–3.68 (1H, m), 3.68–3.80 (1H, m), 3.80–3.90 (1H,m), 3.90–4.02 (1H, m), 4.11–4.18 (1H, m), 7.11 (1H, d, J=8.8 Hz), 7.27(1H, d, J=8.8 Hz), 7.50 (1H, d, J=8.3 Hz), 8.00 (1H, s), 12.86 (1H, s).

EXAMPLE 786N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofurane-3-carboxamide

¹H-NMR (DMSO-d₆) δ; 1.14–1.31 (2H, m), 1.39–1.55 (2H, m), 1.75–1.87 (2H,m), 1.87–2.06 (4H, m), 2.37 (3H, s), 2.80–2.92 (1H, m), 3.50–3.73 (4H,m), 3.81 (1H, t, J=8.1 Hz), 3.95–4.06 (1H, m), 4.11–4.18 (1H, m), 7.12(1H, d, J=8.8 Hz), 7.27 (1H, d, J=8.8 Hz), 7.82 (1H, d, J=8.3 Hz), 8.00(1H, s), 12.85 (1H, s).

EXAMPLE 7872-Dimethylamino-N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

¹H-NMR (DMSO-d₆) δ; 1.22–1.55 (4H, m), 1.70–1.82 (2H, m), 1.91–2.04 (2H,m), 2.14 (6H, s), 2.37 (3H, s), 2.80 (2H, s), 3.55–3.70 (1H, m),3.95–4.06 (1H, m), 7.11 (1H, d, J=9.0 Hz), 7.27 (1H, d, J=8.8 Hz), 8.00(1H, s), 12.86 (1H, s).

EXAMPLE 788 Synthesis ofN-cyclopropylmethyl-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

TheN-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopropanecarboxamide(0.108 g, 0.35 mmol) obtained in Example 35 was added to a suspension oflithium aluminum hydride (0.040 g, 1.1 mmol) in tetrahydrofuran (2 ml),and the resulting mixture was stirred with heating under reflux for 7hours. The resulting solution was cooled on an ice bath, and water (0.02ml), a 2N-aqueous sodium hydroxide solution (0.04 ml) and water (0.08ml) were added dropwise thereto in that order. Then, the insolublematerial was removed by filtration using Celite. The filtrate waspurified by elution by a silica gel chromatography (hexane/ethylacetate/triethylamine=5:15:1) to obtainN-cyclopropylmethyl-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine(82.3 mg, 80%).

Melting point: 132–134° C.

The following compound of Example 789 was synthesized by carrying outreaction according to the method described in Example 788, except forusing theN-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopentanecarboxamideobtained in Example 783, as a starting material.

EXAMPLE 789N-cyclopentylmethyl-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

Melting point: 180° C.

The following compound of Example 790 was synthesized by carrying outreaction according to the method described in Example 788, except forusing the2-methoxy-N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamideobtained in Example 784, as a starting material.

EXAMPLE 790N-(2-methoxyethyl)-N-trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine

IR (neat) cm⁻¹; 1508, 1220, 1093, 941.

The following compound of Example 791 was synthesized by carrying outreaction according to the method described in Example 788, except forusing theN-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofurane-2-carboxamideobtained in Example 785, as a starting material.

EXAMPLE 791N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-2-ylmethyl)amine

IR (neat) cm⁻¹; 1508, 1220, 1072, 941.

The following compound of Example 792 was synthesized by carrying outreaction according to the method described in Example 788, except forusing theN-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofurane-3-carboxamideobtained in Example 786, as a starting material.

EXAMPLE 792N-trans-{4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-3-ylmethyl)amine

IR (neat) cm⁻¹; 1508, 1223, 1092, 943.

EXAMPLE 793 Methyl3-({trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amino)propanoate

A mixture of the trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine(98.1 mg, 0.40 mmol) obtained in Example 408, methyl methacrylate (43mg, 0.50 mmol) and methanol (2.0 ml) was stirred at 50° C. for 6 hours.The solvent was distilled off and the residue oil was subjected toelution by a silica gel column chromatography (ethyl acetate→ethylacetate/triethylamine=20:1) to obtain methyl3-({trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-amino}propanoate(121 mg, 91%).

¹H-NMR (DMSO-d₆) δ; 0.95–1.13 (2H, m), 1.32–1.60 (3H, m), 1.90–2.02 (4H,m), 2.30–2.45 (5H, m), 2.58–2.67 (2H, s), 3.57 (3H, s), 3.96–4.07 (1H,m), 7.10 (1H, d, J=9.0 Hz), 7.26 (1H, d, J=8.8 Hz), 7.99 (1H, s), 12.84(1H, s).

EXAMPLE 794 Synthesis of4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole (a)Synthesis oftrans-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexylamine

A mixture of the trans-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexylamine(245 mg, 1.00 mmol) obtained in Example 408, pyridiniump-toluenesulfonate (50 mg, 0.20 mmol), p-toluenesulfonic acidmonohydrate (380 mg, 2.00 mmol) and N-methylpyrrolidone (5.0 ml) wasstirred at 90° C. for 13 hours. A 1N-aqueous sodium hydroxide solution(30 ml) was added to the reaction solution, followed by extraction withchloroform (20 ml) (twice). The extract solution was dried overmagnesium sulfate and then concentrated to dryness, and the residue oilwas purified by elution by a silica gel column chromatography(chloroform/methanol=50:1→chloroform/methanol/triethylamine=20:1:1) toobtaintrans-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexylamine(215 mg, 65%).

¹H-NMR (CDCl₃) δ; 1.08–2.20 (12H, m), 2.40–2.62 (5H, m), 2.71–2.85 (1H,m), 3.68–3.80 (1H, m), 3.92–4.07 (2H, m), 5.66 (1H, dd, J=9.4 Hz, 2.6Hz), 7.10 (1H, d, J=9.0 Hz), 7.34 (1H, d, J=9.2 Hz), 7.97 (1H, s).

(b) Synthesis of4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole

A mixture oftrans-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexylamine(106 mg, 0.321 mmol), 1,4-dibromobutane (69.3 mg, 0.321 mmol), potassiumcarbonate (110 mg, 0.80 mmol) and N,N-dimethylacetamide (2.0 ml) wasstirred at 80° C. for 2 hours. A 1N-aqueous sodium hydroxide solution(20 ml) was added to the reaction solution, followed by extraction withchloroform (20 ml) (twice). The extract solution was dried overmagnesium sulfate and then concentrated to dryness, and the residue oilwas purified by elution by a silica gel column chromatography(hexane/ethyl acetate=1:2→hexane/ethyl acetate/triethylamine=20:40:3) toobtain4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(67.1 mg, 55%).

¹H-NMR (CDCl₃) δ; 0.75–2.20 (16H, m), 2.43–2.65 (9H, m), 3.68–3.80 (1H,m), 3.92–4.07 (2H, m), 5.62–5.68 (1H, m), 7.10 (1H, d, J=9.0 Hz), 7.34(1H, d, J=9.2 Hz), 7.96 (1H, s)

(c) Synthesis of4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole

A mixture of4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(62.1 mg, 0.162 mmol), a 4N-hydrochloric acid/dioxane solution (2.0 ml)and isopropanol (2.0 ml) was stirred at room temperature for 4 hours.The solvent was distilled off and a 1N-aqueous sodium hydroxide solution(20 ml) was added to the residue, followed by extraction with ethylacetate (20 ml) (twice). The extract solution was dried over magnesiumsulfate and then concentrated to dryness, and the residue oil waspurified by elution by a silica gel column chromatography (hexane/ethylacetate/triethylamine=20:40:3) to obtain4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole (28.3mg, 58%).

IR (neat) cm⁻¹; 1506, 1217, 1097, 941.

The following compounds of Example 795 to Example 802 were synthesizedaccording to the processes described in Example 455 and Example 461,except for using thecis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example410, as a starting material.

EXAMPLE 795 Synthesis ofN-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-pentylamine (a)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}pentanamide

MS: m/z=330 (M+1)

(b) N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-pentylamine

IR (neat) cm⁻¹; 2933, 2852, 1225, 1095, 939, 787.

EXAMPLE 796 Synthesis ofN-isobutyl-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine (a)2-methyl-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

MS: m/z=316 (M+1)

(b) N-isobutyl-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 2935, 2864, 1228, 1103, 953, 943, 796.

EXAMPLE 797 Synthesis ofN-(2-methoxyethyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine(a)2-methoxy-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

MS: m/z=318 (M+1)

(b)N-(2-methoxyethyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.54–1.78 (8H, m), 2.03–2.07 (2H, m), 2.49 (3H, s),2.60 (1H, m), 2.86 (2H, t, J=5.2 Hz), 3.38 (3H, s), 3.55 (2H, t, J=5.2Hz), 3.70 (1H, m), 4.36 (1H, m), 7.08 (1H, d, J=8.8 Hz), 7.24 (1H, d,J=8.8 Hz), 8.01 (1H, d, J=0.92 Hz)

EXAMPLE 798 Synthesis ofN-(cyclopropylmethyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine(a)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopropanecarboxamide

MS: m/z=314 (M+1)

(b)N-(cyclopropylmethyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 0.11–0.16 (2H, m), 0.44–0.52 (2H, m), 1.01 (1H, m),1.53–1.78 (6H, m), 2.02–2.07 (2H, m), 2.46 (3H, s), 2.55 (2H, d, J=7.0Hz), 2.61–2.68 (1H, m), 4.34 (1H, m), 7.05 (1H, d, J=8.9 Hz), 7.24 (1H,d, J=8.9 Hz), 8.02 (1H, d, J=0.92 Hz).

EXAMPLE 799 Synthesis ofN-(cyclopentylmethyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine(a)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopentanecarboxamide

MS: m/z=342 (M+1)

(b)N-(cyclopentylmethyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 2929, 2862, 1223, 1090, 939, 914, 795.

EXAMPLE 800 Synthesis ofN-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-2-ylmethyl)amine(a)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofuran-2-carboxamide

MS: m/z=344 (M+1)

(b)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-2-ylmethyl)amine

¹H-NMR (CDCl₃) δ; 1.50–1.80 (7H, m), 1.83–2.07 (5H, m), 2.48 (3H, s),2.56–2.63 (1H, m), 2.68 (1H, dd, J=12, 8.0 Hz), 2.79 (1H, dd, J=12, 3.8Hz), 3.73–3.80 (1H, m), 3.84–3.91 (1H, m), 4.00–4.08 (1H, m), 4.34 (1H,m), 7.07 (1H, d, J=8.9 Hz), 7.24 (1H, d, J=8.9 Hz), 8.02 (1H, d, J=0.92Hz).

EXAMPLE 801 Synthesis ofN-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-3-ylmethyl)amine(a)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofuran-3-carboxamide

MS: m/z=344 (M+1)

(b)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-3-ylmethyl)amine

¹H-NMR (CDCl₃) δ; 1.55–1.75 (7H, m), 2.02–2.13 (3H, m), 2.33–2.45 (1H,m), 2.49 (3H, s), 2.53–2.63 (1H, m), 2.68 (2H, d, J=7.7 Hz), 3.52 (1H,dd, J=8.4, 6.1 Hz), 3.72–3.79 (1H, m), 3.84–3.95 (1H, m), 4.32 (1H, m),7.07 (1H, d, J=8.9 Hz), 7.24 (1H, d, J=8.9 Hz), 8.02 (1H, d, J=0.92 Hz).

EXAMPLE 802 Synthesis ofN-benzyl-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine (a)N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}benzamide

MS: m/z=350 (M+1)

(b) N-benzyl-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.54–1.83 (6H, m), 2.02–2.08 (2H, m), 2.50 (3H, s),2.66 (1H, m), 3.69 (1H, m), 3.87 (2H, s), 4.33 (1H, m), 7.08 (1H, d,J=9.0 Hz), 7.22 (1H, d, J=9.0 Hz), 7.22–7.39 (5H, m), 8.02 (1H, d,J=0.92 Hz).

The following compounds of Example 803 to Example 807 were synthesizedaccording to the process described in Example 423, except for using thecis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example410, as a starting material.

EXAMPLE 803N-(2-chlorobenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.56–1.65 (2H, m), 1.73–1.83 (4H, m), 2.01–2.10 (2H,m), 2.47 (3H, s), 2.72 (1H, m), 4.00 (2H, s), 4.35 (1H, m), 7.07 (1H, d,J=9.0 Hz), 7.17–7.50 (5H, m), 8.00 (1H, s).

EXAMPLE 804N-(3-chlorobenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.54–1.77 (6H, m), 2.02–2.07 (2H, m), 2.48 (3H, s),2.65 (1H, m), 3.84 (2H, s), 4.32 (1H, m), 7.06 (1H, d, J=9.0 Hz),7.19–7.25 (4H, m), 7.35 (1H, s), 8.02 (1H, d, J=0.92 Hz).

EXAMPLE 805N-(4-chlorobenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.55–1.75 (6H, m), 2.02–2.08 (2H, m), 2.51 (3H, s),2.62 (1H, m), 3.82 (2H, s), 4.33 (1H, m), 7.09 (1H, d, J=8.9 Hz), 7.24(1H, d, J=8.9 Hz), 7.29 (4H, s), 8.03 (1H, d, J=0.55 Hz).

EXAMPLE 806N-(2-furylmethyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.59–1.77 (6H, m), 2.03–2.08 (2H, m), 2.48 (3H, s),2.66 (1H, m), 3.89 (2H, s), 4.36 (1H, m), 6.21 (1H, d, J=3.1 Hz), 6.32(1H, m), 7.08 (1H, d, J=9.0 Hz), 7.24 (1H, d, J=9.0 Hz), 7.37 (1H, m),8.01 (1H, s).

EXAMPLE 807N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(thien-2-ylmethyl)amine

¹H-NMR (CDCl₃) δ; 1.54–1.77 (6H, m), 2.02–2.08 (2H, m), 2.49 (3H, s),2.72 (1H, m), 4.08 (2H, s), 4.34 (1H, m), 6.95–6.97 (2H, m), 7.08 (1H,d, J=9.0 Hz), 7.20–7.25 (2H, m), 8.02 (1H, d, J=1.1 Hz).

EXAMPLE 808N-(2-fluorobenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.54–1.78 (6H, m), 2.02–2.08 (2H, m), 2.50 (3H, s),2.63 (1H, m), 3.92 (2H, s), 4.33 (1H, m), 7.00–7.13 (3H, m), 7.20–7.27(2H, m), 7.37 (1H, dt-like, J=7.5, 1.8 Hz), 8.02 (1H, d, J=0.92 Hz).

EXAMPLE 809N-(3-fluorobenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.54–1.76 (6H, m), 2.01–2.08 (2H, m), 2.49 (3H, s),2.64 (1H, m), 3.86 (2H, s), 4.32 (1H, m), 6.93 (1H, m), 7.05–7.12 (3H,m), 7.20–7.31 (2H, m), 8.03 (1H, d, J=0.92 Hz).

EXAMPLE 810N-(4-fluorobenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

¹H-NMR (CDCl₃) δ; 1.53–1.80 (6H, m), 2.02–2.07 (2H, m), 2.47 (3H, s),2.68 (1H, m), 3.87 (2H, s), 4.33 (1H, m), 6.96–7.06 (3H, m), 7.22 (1H,d, J=8.8 Hz), 7.31–7.35 (2H, m), 8.00 (1H, d, J=0.92 Hz).

EXAMPLE 811N-(2-methoxybenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 2943, 1497, 1250, 1227, 1126, 941, 752.

EXAMPLE 812N-(3-methoxybenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 2939, 1265, 1221, 1039, 941, 785.

EXAMPLE 813N-(4-methoxybenzyl)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amine

IR (neat) cm⁻¹; 2945, 1508, 1250, 941, 750.

The following compounds of Examples 814 and 815 were synthesizedaccording to the process described in Example 455, except for using thecis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example410, as a starting material.

EXAMPLE 8143,3,3-Trifluoro-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

MS: m/z=356 (M+1)

EXAMPLE 8152-(Benzyloxy)-N-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

MS: m/z=394 (M+1)

EXAMPLE 816 Synthesis of4-methyl-5-[(4-morpholin-cis-4-ylcyclohexyl)oxy]-1H-indazolehydrochloride (a) Synthesis of2-{cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione

To a solution of2-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(100 mg, 0.266 mmol) in tetrahydrofuran (2.7 ml) were added3,4-dihydro-2H-pyran (36 μl, 0.399 mmol) and p-toluenesulfonic acidmonohydrate (15 mg, 0.069 mmol), and the resulting mixture was stirredfor 4 hours while being maintained at 70° C. The reaction solution wasallowed to cool, and then was concentrated under reduced pressure toobtain a crude product. The crude product was purified by a silica gelcolumn chromatography (eluent: hexane/ethyl acetate) to obtain2-{cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(99.6 mg, 82%).

(b) Synthesis ofcis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine

A mixture of2-{cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione(95.5 mg, 0.208 mmol) and a 30% methylamine-ethanol solution (5.0 ml)was stirred with heating under reflux for 2 hours. The reaction solutionwas allowed to cool, and then was concentrated under reduced pressure toobtain a crude product. The crude product was purified by a silica gelcolumn chromatography (eluent: chloroform/methanol/28% aqueous ammonia)to obtaincis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine(60.4 mg, 88%).

(c) Synthesis of4-methyl-5-[(4-morpholin-cis-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole

To a solution ofcis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine(200 mg, 0.607 mmol) in N,N-dimethylformamide (4.0 ml) were addedbis-2-bromoethyl ether (76.4 μl, 0.607 mmol) and potassium carbonate(252 mg, 1.82 mmol), and the resulting mixture was stirred for 6 hourswhile being maintained at 80° C. The reaction solution was allowed tocool, and then was filtered, and the filtrate was concentrated underreduced pressure to obtain a crude product. The crude product waspurified by a silica gel column chromatography (eluent:chloroform/methanol) to obtain4-methyl-5-[(4-morpholin-cis-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(186 mg, 77%).

(d) Synthesis of4-methyl-5-[(4-morpholin-cis-4-ylcyclohexyl)oxy]-1H-indazoleHydrochloride

To a solution of4-methyl-5-[(4-morpholin-cis-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole(186 mg, 0.465 mmol) in 2-propanol (4.0 ml) was added 4N-hydrochloricacid-dioxane (4.0 ml, 16 mmol), and the resulting mixture was stirredfor 24 hours while being maintaining at room temperature. The whiteprecipitate formed was collected by filtration and dried under reducedpressure to obtain4-methyl-5-[(4-morpholin-cis-4-ylcyclohexyl)oxy]-1H-indazolehydrochloride (149 mg, 91%).

¹H-NMR (DMSO-d₆) δ; 1.56 (2H, m), 1.80–2.08 (6H, m), 2.45 (3H, s),3.08–3.15 (2H, m), 3.24 (1H, m), 3.42 (2H, d-like, J=12.1 Hz), 3.85–3.98(4H, m), 4.48 (1H, m), 7.12 (1H, d, J=8.9 Hz), 7.29 (1H, d, J=8.9 Hz),8.02 (1H, d, J=0.92 Hz), 10.97 (1H, brs).

The following compounds of Examples 817 and 818 were synthesizedaccording to the process described in Example 423, except for using thecis-5-[(3-aminocyclohexyl)oxy]-1H-indazole-4-carbonitrile obtained inExample 693, as a starting material.

EXAMPLE 817cis-5-{[3-(Benzylamino)cyclohexyl]oxy}-1H-indazole-4-carbonitrile

IR (neat) cm⁻¹; 2939, 2222, 1495, 1313, 1236, 1028, 945, 750.

EXAMPLE 818cis-5-{[3-(Dimethylamino)cyclohexyl]oxy}-1H-indazole-4-carbonitrile

IR (neat) cm⁻¹; 2937, 2218, 1498, 1311, 1242, 1022, 947, 795.

EXAMPLE 819 Synthesis of2-methyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

Isobutyric acid (36.2 μL, 0.39 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (74.8mg, 0.39 mmol), hydroxybenzotriazole (52.8 mg, 0.39 mmol) andtriethylamine (0.18 ml, 1.28 mmol) were added to a solution ofmonohydrochloride (100 mg, 0.35 mmol) of thecis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example411 in N,N-dimethylformamide (5 ml), and the resulting mixture wasstirred overnight at room temperature. The reaction solution waspartitioned by the addition of ethyl acetate, toluene and water, andthen extracted twice with ethyl acetate-toluene (1/1). The extractsolution was washed with a saturated aqueous sodium hydrogencarbonatesolution and then dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure and the resulting residue waspurified by a silica gel column chromatography (eluent: hexane/ethylacetate=1/1 to 0/1) to obtain2-methyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide(86.3 mg, 77%).

IR (neat) cm⁻¹; 953, 1086, 1215, 1543, 1635.

The following compounds of Examples 820 to 826 were synthesized bycarrying out reaction according to the method described in Example 819.

EXAMPLE 820N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofuran-3-carboxamide

IR (neat) cm⁻¹; 954, 1031, 1215, 1514, 1543, 1633.

EXAMPLE 8212-Methoxy-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

IR (neat) cm⁻¹; 953, 1112, 1232, 1512, 1647.

EXAMPLE 8223,3,3-Trifluoro-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

IR (neat) cm⁻¹; 1013, 1084, 1146, 1552, 1655.

EXAMPLE 823N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopropanecarboxamide

IR (neat) cm⁻¹; 955, 1086, 1217, 1551, 1633.

EXAMPLE 8242,2-Dimethyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

IR (neat) cm⁻¹; 951, 1200, 1535, 1628, 2945.

EXAMPLE 8252-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

LC/MS: M+1=433.4

EXAMPLE 826N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}isonicotinamide

IR (neat) cm⁻¹; 650, 945, 1009, 1537, 1633.

EXAMPLE 827 Synthesis ofN-isobutyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amineMonohydrochloride

Lithium aluminum hydride (45.6 mg, 1.20 mmol) was added to a THFsolution (5 ml) of the2-methyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide(76 mg, 0.24 mmol) obtained in Example 819, and the resulting mixturewas stirred with heating at 85° C. for 12 hours. The reaction solutionwas cooled, and water (46 μl), a 2N-aqueous sodium hydroxide solution(92 μl) and then water (138 μl) were added thereto and stirred for 30minutes, followed by filtration using Celite. The residue was purifiedby a silica gel chromatography (ethyl acetate, methanol (5% aqueousammonia):chloroform=1/10). To a solution of the purified residue in2-propanol was added a 1N-hydrochloric acid-diethyl ether solution (0.25mL), and stirred for 30 minutes, and the solvent was distilled off underreduced pressure. Then, the residue was crystallized from2-propanol-diisopropyl ether-diethyl ether to obtainN-isobutyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride (42.0 mg, 49%).

LC/MS: M+1=302.3

EXAMPLE 828 Synthesis ofN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-3-ylmethyl)amineMonohydrochloride

N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(tetrahydrofuran-3-ylmethyl)aminemonohydrochloride was obtained according to the process described inExample 827, except for using theN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}tetrahydrofuran-3-carboxamideobtained in Example 820.

IR (neat) cm⁻¹; 1041, 1090, 1223, 1510, 2943.

EXAMPLE 829 Synthesis ofN-(2-methoxyethyl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amineMonohydrochloride

N-(2-methoxyethyl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride was obtained according to the process described inExample 827, except for using the2-methoxy-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamideobtained in Example 821.

LC/MS: M+1=304.2

EXAMPLE 830 Synthesis ofN-(cyclopropylmethyl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amineMonohydrochloride

N-(cyclopropylmethyl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride was obtained according to the process described inExample 827, except for using theN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}cyclopropanecarboxamideobtained in Example 823.

IR (neat) cm⁻¹; 800, 1211, 1267, 1529, 2611.

EXAMPLE 831 Synthesis ofN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-neopentylamineMonohydrochloride

N-(3,3-dimethylbutyl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride was obtained according to the process described inExample 827, except for using the2,2-dimethyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamideobtained in Example 824.

IR (neat) cm⁻¹; 1115, 1227, 1375, 1518, 2953.

EXAMPLE 832 Synthesis ofN˜1˜-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}glycinamidemonohydrochloride

A 40% methylamine methanolic solution (5 mL) was added to the2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide(70 mg, 0.16 mmol) obtained in Example 825, and the resulting mixturewas stirred overnight. The reaction solution was distilled under reducedpressure to remove the solvent and then the residue was purified by asilica gel chromatography. To a solution of the purified residue in2-propanol was added a hydrochloric acid-diethyl ether solution, andstirred for 30 minutes. After the solvent was distilled off underreduced pressure, the residue was crystallized from2-propanol-diisopropyl ether-diethyl ether to obtain N˜1˜(identificationisrequired)-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}glycinamidemonohydrochloride (39 mg, 79%).

IR (neat) cm⁻¹; 1201, 1267, 1556, 1662, 2943.

EXAMPLE 833 Synthesis ofN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(pyridin-4-ylmethyl)amine

Isonicotinaldehyde (42.8 μl, 0.45 mmol) and acetic acid (0.23 mL, 4.08mmol) were added to a methanolic solution (5 ml) of thecis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.41 mmol)obtained in Example 411, and the resulting mixture was stirred for 10minutes. Then, sodium cyanoborohydride (28.2 mg, 0.45 mmol) was addedthereto and stirred for 2 hours. An aqueous sodium hydroxide solutionwas added to the reaction solution, followed by extraction withchloroform (three times), and the extract solution was dried overanhydrous magnesium sulfate. The residue was purified by a silica gelchromatography (ethyl acetate, methanol (5% aqueous ammonia):chloroform=10/100) to obtainN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(pyridin-4-ylmethyl)amine(58.7 mg, 43%).

IR (neat) cm⁻¹; 941, 1092, 1221, 1508, 1603, 2933.

The following compounds of Example 834 to Example 836 were synthesizedby carrying out reaction according to the method described in Example833.

EXAMPLE 834N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(pyridin-3-ylmethyl)aminemonohydrochloride

LC/MS: M+1=337.3

EXAMPLE 835N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(pyridin-2-ylmethyl)amine

IR (neat) cm⁻¹; 939, 1092, 1221, 1732, 2935.

EXAMPLE 836 EthylN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}glycinate

LC/MS: M+1=332.5

EXAMPLE 837 Synthesis of2-({cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amino)ethanol

The ethyl N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}glycinateobtained in Example 836 was added to a tetrahydrofuran suspension oflithium aluminum hydride, and the resulting mixture was stirred at roomtemperature for 3 hours. Water, a 2N-aqueous sodium hydroxide solutionand then water were added to the reaction mixture and stirred for 1hour, followed by filtration using Celite. The filtrate was concentratedand then purified by a preparative thin-layer chromatography (methanol(containing aqueous ammonia)/chloroform=1/10) to obtain2-({cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amino)ethanol (17.6mg, 40%).

IR (neat) cm⁻¹; 943, 1057, 1093, 1223, 3188.

EXAMPLE 838 Synthesis of methylN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-β-alaniate

Methyl acrylate (0.04 mL, 0.49 mmol) was added to a methanolic solution(5 mL) of the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100mg, 0.41 mmol) obtained in Example 411, and the resulting mixture wasstirred with heating at 50° C. for 2 hours. The reaction solution wasconcentrated under reduced pressure and then purified by a silica gelchromatography (ethyl acetate, methanol/chloroform=1/10) to obtainmethyl N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-β-alaniate(88.0 mg, 65%).

LC/MS: M+1=332.2

The compound of Example 839 was synthesized by carrying out reactionaccording to the method described in Example 838.

EXAMPLE 839 tert-ButylN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-β-alaniate

LC/MS: M+1=374.3

EXAMPLE 840 Synthesis ofN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-β-alaninebis(trifluoroacetate)

A dichloromethane solution (5 mL) of the tert-butylN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-β-alaniate (106 mg,0.28 mmol) obtained in Example 839 was added to a solution oftrifluoroacetic acid (5 mL) in dichloromethane (5 mL) at 0° C. andstirred at room temperature for 2 hours. The reaction solution wasdistilled under reduced pressure to remove the solvent, followed byazeotropic distillation with toluene, wherebyN-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-β-alaninebis(trifluoroacetate) (196.2 mg, quant.) was obtained.

LC/MS: M+1=318.2

EXAMPLE 841 Synthesis oftrans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine

Acetic acid (0.14 mL, 2.5 mmol) and an aqueous formaldehyde solution(209.3 mg, 2.5 mmol) were added to a methanolic solution (3 mL) of thetrans-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine (130 mg, 0.5 mmol)obtained in Example 744, and then sodium cyanoborohydride (157.7 mg, 2.5mmol) was added thereto and stirred overnight. A 1N-aqueous sodiumhydroxide solution was added to the reaction solution, followed byextraction with chloroform (three times), and the extract solution wasdried over anhydrous magnesium sulfate. The residue was purified by asilica gel chromatography (methanol:chloroform=0/100 to 10/100) toobtaintrans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylamine(82.3 mg, 57%).

IR (neat) cm⁻¹; 798, 895, 947, 1057, 1498.

EXAMPLE 842 Synthesis ofN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylaminemonohydrochloride

Reaction was carried out according to the method described in Example841, except for using thecis-3-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtained in Example745. To a 2-propanol solution (5 ml) of the resulting purified product(125 mg) was added a 1N-hydrochloric acid/diethyl ether solution (0.88mL), and stirred for 30 minutes. The solvent was distilled off underreduced pressure and then the residue was crystallized from2-propanol-diisopropyl ether-diethyl ether to obtainN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylaminemonohydrochloride (85.2 mg, 46%).

IR (neat) cm⁻¹; 982, 1036, 1211, 1257, 1525.

EXAMPLE 843 Synthesis ofcis-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylaminemonohydrochloride

Except for using the cis-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamineobtained in Example 746,cis-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylaminemonohydrochloride was obtained according to the process described inExample 842.

IR (neat) cm⁻¹; 843, 943, 997, 1242, 1446.

EXAMPLE 844 Synthesis ofN-{trans-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylaminemonohydrochloride

N-{trans-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N,N-dimethylaminemonohydrochloride was obtained according to the process described inExample 842, except for usingtrans-3-((4-methyl-1H-indazol-5-yl)oxy)cyclohexanamine.

IR (neat) cm⁻¹; 804, 841, 1211, 1259, 1527.

EXAMPLE 845 Synthesis oftrans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

Except for using thetrans-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtained inExample 744,trans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide wasobtained according to the process described in Example 819.

IR (neat) cm⁻¹; 1111, 1321, 1551, 1624, 2937.

EXAMPLE 846

Synthesis oftrans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

Except for using thetrans-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtained inExample 744,trans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide wasobtained according to the process described in Example 819.

IR (neat) cm⁻¹; 1119, 1231, 1545, 1633, 2933.

EXAMPLE 847 Synthesis ofN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

N-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide was obtainedaccording to the process described in Example 819, except for using thecis-3-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtained in Example745.

IR (neat) cm⁻¹; 957, 1111, 1232, 1545, 1632.

EXAMPLE 848 Synthesis ofcis-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

Except for using the cis-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamineobtained in Example 746,cis-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide was obtainedaccording to the process described in Example 819.

LC/MS: M+1=302.3

EXAMPLE 849 Synthesis ofN-{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide

N-{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide wasobtained according to the process described in Example 819, except forusing the trans-3-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtainedin Example 747.

LC/MS: M+1=302.3

EXAMPLE 850 Synthesis oftrans-N-ethyl-4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride

Except for using thetrans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide obtainedin Example 845,trans-N-ethyl-4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexanaminemonohydrochloride was obtained according to the process described inExample 827.

IR (neat) cm⁻¹; 791, 845, 1059, 1213, 1524.

EXAMPLE 851 Synthesis oftrans-4-[(4-ethyl-1H-indazol-5-yl)oxy]-N-propylcyclohexanaminemonohydrochloride (a) Synthesis oftrans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

Except for using thetrans-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtained inExample 744,trans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide wasobtained according to the process described in Example 819.

(b) Synthesis oftrans-4-[(4-ethyl-1H-indazol-5-yl)oxy]-N-propylcyclohexanaminemonohydrochloride

Except for usingtrans-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide,trans-4-[(4-ethyl-1H-indazol-5-yl)oxy]-N-propylcyclohexanaminemonohydrochloride was obtained according to the process described inExample 827.

¹H-NMR (DMSO-d₆) δ; 0.90 (t, 3H), 1.17 (t, 3H), 1.45 (q, 4H), 1.63 (m,2H), 2.09 (m, 4H), 2.84 (m, 4H), 3.03 (m, 1H), 4.06 (m, 1H), 7.16 (d,1H, J=8.89 Hz), 7.29 (d, 1H, J=8.89 Hz), 8.03 (s, 1H), 8.77 (br, 1H),8.89 (br, 1H).

EXAMPLE 852 Synthesis ofN-ethyl-N-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride

N-ethyl-N-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride was obtained according to the process described inExample 827, except for using theN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide obtained inExample 847.

IR (neat) cm⁻¹; 799, 1036, 1211, 1257, 1527.

EXAMPLE 853 Synthesis ofN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylaminemonohydrochloride (a) Synthesis ofN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide

N-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide wasobtained by carrying out reaction according to the method described inExample 819, except for using thecis-3-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtained in Example745.

(b) Synthesis ofN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylaminemonohydrochloride

N-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylaminemonohydrochloride was obtained by carrying out reaction according to themethod described in Example 827, except for usingN-{cis-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide.

IR (neat) cm⁻¹; 1012, 1207, 1257, 1456, 1527.

EXAMPLE 854 Synthesis ofcis-N-ethyl-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride

Except for using thecis-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide obtained inExample 848,cis-N-ethyl-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride was obtained according to the process described inExample 827.

IR (neat) cm⁻¹; 812, 1045, 1217, 1261, 1525.

EXAMPLE 855

Synthesis ofcis-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylaminemonohydrochloride

Except for using the cis-4-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamineobtained in Example 746,cis-N-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylaminemonohydrochloride was obtained according to the process described inExample 853.

IR (neat) cm⁻¹; 800, 1217, 1261, 1525, 2939.

EXAMPLE 856 Synthesis ofN-ethyl-N-{trans-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride

N-ethyl-N-{trans-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}aminemonohydrochloride was obtained according to the process described inExample 827, except for using theN-{trans-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}acetamide obtainedin Example 849.

IR (neat) cm⁻¹; 800, 1221, 1257, 1458, 1527, 2943.

EXAMPLE 857 Synthesis ofN-{trans-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylaminemonohydrochloride

N-{trans-3-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-propylaminemonohydrochloride was obtained according to the process described inExample 853, except for using thetrans-3-((4-ethyl-1H-indazol-5-yl)oxy)cyclohexanamine obtained inExample 747.

IR (neat) cm⁻¹; 1221, 1257, 1458, 1525, 2939.

EXAMPLE 858 Synthesis of5-{(2S*4R*6S*)-[(2,6-dimethylpiperidin-4-yl)oxy]}-4-methyl-1H-indazolehydrochloride (a) Synthesis oft-butyl(2S*4R*6S*)-4-hydroxy-2,6-dimethylpiperidine-1-carbonate

Triethylamine (1.67 ml, 12.0 mmol) and di-tert-butyl dicarbonate (2.76ml, 12.0 mmol) were added to a solution of(2S*4S*6S*)-2,6-dimethyl-4-hydroxypiperidine hydrochloride (388 mg, 3.00mmol) in dimethylformamide (6 ml), and the resulting mixture was stirredat 60° C. for 3 hours. Then, di-tert-butyl dicarbonate (1.38 ml, 6.0mmol) was added thereto and the resulting mixture was stirred at 60° C.for another 2 hours. The reaction was terminated by the addition ofwater and 5%-potassium hydrogensulfate, followed by extraction withethyl acetate-toluene (1:1). The extract solution was washed with asaturated aqueous sodium chloride solution, dried over sodium sulfate,and then distilled under reduced pressure to remove the solvent, wherebyt-butyl(2S*4R*6S*)-4-hydroxy-2,6-dimethylpiperidine-1-carbonate (373 mg,54%) was obtained.

(b) Synthesis of5-{(2S*4R*6S*)-[(2,6-dimethylpiperidin-4-yl)oxy]}-4-methyl-1H-indazolehydrochloride

To a toluene solution (4 ml) of t-butyl(2S*4R*6S*)-4-hydroxy-2,6-dimethylpiperidine-1-carbonate (144 mg, 0.628mmol) were added 4-methyl-1H-indazol-5-ol (140 mg, 0.945 mol) andcyanomethylenetri-n-butylphosphorane (253 mg, 0.943 mmol), and theresulting mixture was stirred at 100° C. for 5 hours. The solvent wasdistilled off under reduced pressure, and the residue was diluted withchloroform and then washed with a 1N-aqueous sodium hydroxide solution.Thereafter, the solvent was distilled off under reduced pressure.Methanol (3 ml) and 4N-hydrochloric acid-dioxane (3 ml) were added tothe residue, and the resulting mixture was stirred at room temperaturefor 1 hour. After the solvent was distilled off, the residue wascrystallized from methanol-ethyl acetate to obtain5-{(2S*4R*6S*)-[(2,6-dimethylpiperidin-4-yl)oxy]}-4-methyl-1H-indazolehydrochloride (30 mg, 16%).

IR (neat) cm⁻¹; 1283, 1219, 1209, 1151, 997, 941.

TEST EXAMPLE 1

Assay of the inhibition of phosphorylation by Rho kinase

A bovine brain extract fraction was prepared as follows. That is, graymatter was minced off from bovine brain and suspended in a buffersolution for immunoprecipitation (10 mM tris(hydroxymethyl)aminomethane(Tris) (pH 7.5), 1% Triton X-100, 0.5% NP-40, 150 mM NaCl, 20 mM sodiumfluoride, 1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM ethyleneglycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) and 0.2mM phenylmethylsulfonyl fluoride (PMSF)) in 2 volumes of the graymatter. The tissue was homogenized by the use of a Potter typehomogenizer made of polytetrafluoroethylene. After centrifugation at20,000 g for 15 minutes, the supernatant was collected and thensubjected to ultracentrifugation at 100,000 g for 60 minutes. Thesupernatant was used as a bovine extract fraction.

An anti-Rho kinase antibody immobilized plate was prepared as follows.That is, a secondary antibody (anti-goat IgG (Fc) antibody) was dilutedwith phosphate-buffered saline: PBS) 300-fold (1 μl antibody/300 μlPBS), and 100 μl of the resulting dilution was added to each well of a96-well ELISA plate. After coating at room temperature for 2 hours, thesupernatant was removed. Thereafter, 100 μl of PBS was added and thenthe supernatant was removed (this washing operation was carried outtwice). After the washing, 100 μl of a blocking buffer solution (0.05%Tween 20 and 0.25% bovine serum albumin (fatty acid free)/PBS) wasadded, followed by blocking at room temperature for 1 hour. After theblocking, each well was washed twice with 100 μl of the blocking buffersolution, and 100 μl of a primary antibody (anti-ROKII (Rho kinase)peptide antibody) diluted 200-fold (0.5 μl (0.1 μg)/100 μl) with PBS wasadded, followed by coating at room temperature for 2 hours. After thecoating, each well was washed once with 100 μl of the blocking buffersolution. In addition, 100 μl of the blocking buffer solution was addedto obtain an anti-Rho kinase antibody immobilized plate.

Using the aforesaid plate, Rho kinase was selectively immobilized fromthe bovine brain extract fraction, and phosphorylation by Rho kinase wasassayed. To each well of the antibody-immobilized plate was added 100 μlof a bovine brain extract solution prepared so as to have aconcentration of 1.5 mg/ml, and the reactions were incubated at 4° C.for 1 hour to immobilize Rho kinase on the plate. After completion ofthe reaction, the supernatant was removed and each well was washed threetimes with 100 μl of the buffer solution for immunoprecipitation. Inaddition, each well was washed three times with 100 μl of buffersolution A (50 mM Tris (pH 7.5), 10 mM MgCl₂ and 150 mM NaCl). To eachwell of the plate freed from the supernatant was added 40 μl of theaforesaid buffer solution for reaction (50 mM Tris-HCl (pH 7.5), 2 mMEDTA and 10 mM MgCl₂). Further, adenosine 5′-triphosphate (ATP) buffer(0.1 μM ATP (containing 6 nM [γ-³²P]ATP) and 10 μg histone (HF2A))containing each compound was prepared, and 10 μl of this solution wasadded to each well of the plate to initiate the reaction. The reactionswere carried out at room temperature for 4 hours. The reactions wereterminated by the addition of a phosphoric acid solution of a finalconcentration of 75 mM and 50 μM ATP. After completion of the reaction,50 μl of the reaction solutions were spotted onto a phosphocellulosefilter for Beta Plate 1205 (Wallac) only. After the spot, the filter waswashed with 150 ml of a 75 mM phosphoric acid solution for 10 minutes.This washing operation was repeated three times. After completion of thewashing, the filter was dried and then wrapped in a cellophane bag, and10 ml of a liquid scintillation cocktail was added. The amount of energy(β-ray radioactivity count) trapped in the filter was measured with BetaPlate 1205.

A count measured for a sample containing no Rho kinase was taken as abackground count (=activity 0%), and a count (thephosphorylating-activity of Rho kinase) measured for a sample containingno compound was taken as activity of 100%. A compound concentration atwhich the phosphorylation reaction was inhibited by 50% was taken as anIC₅₀ value for Rho kinase.

In this test, the IC₅₀ value for Rho kinase of the compound of Example 1was 0.4 μl/ml.

TEST EXAMPLE 2

Inhibitory Effect on the Contraction of the Detrusor of Isolated Bladder

Hartley male guinea pigs (aged about 7 weeks) were killed by a blow onthe head followed by exsaguination, and the bladders were isolated andthen suspended (static tension: 1 g) in a magunus bath with a capacityof 25 ml filled with Krebs-Henseleit solution (118.4 mM NaCl, 25 mMNaHCO₃, 1.2 mM KH₂PO₄, 4.7 mM KCl, 2.5 mM CaCl₂, 1.2 mM MgSO₄ and 11 mMglucose) maintained at 37° C., aerated with 95% O₂-5% CO₂. The tensionof a specimen of the bladder was measured with an isometric transducerand recorded in a recorder through an amplifier (AP-6416, Nihon Kohden).After 45 minutes stabilization, the bladder specimen was contracted byacetylcholine at concentrations of 0.3 to 300 μM. Thereafter, thebladder specimen was washed with Krebs-Henseleit solution to bestabilized, and then a test material was added in an amount of 100μg/ml. From 10 minutes after the addition, the bladder specimen wascontracted again by acetylcholine at concentrations of 0.3 to 300 μM.The inhibitory effect was evaluated on the basis of the rate of bladdercontraction determined by taking the maximum contraction reaction causedby the first acetylcholine addition as 100%. The results are shown inFIG. 1.

INDUSTRIAL APPLICABILITY

The compound of the present invention has inhibitory effect on Rhokinase and is useful as a therapeutic agent for diseases which are suchthat morbidity due to them is expected to be improved by inhibition ofRho kinase and secondary effects such as inhibition of the Na⁺/H⁺exchange transport system caused by the Rho kinase inhibition, forexample, hypertension, peripheral circulatory disorder, angina, cerebralvasospasm, premature birth, and asthma, which are improved by smoothmuscle relaxing effect, and diseases (chronic arterial obstruction andcerebrovascular accident) caused by hyperaggregability of platelet;diseases such as arteriosclerosis, fibroid lung, fibroid liver, liverfailure, fibroid kidney, renal glomerulosclerosis, kidney failure, organhypertrophy, prostatic hypertrophy, complications of diabetes, bloodvessel restenosis, and cancer, which are improved by inhibitory effecton cell over-proliferation•emigration•fibrosing (e.g. fibroblastproliferation, smooth muscle cell proliferation, mesangial cellproliferation and hemoendothelial cell proliferation); cardiachypertrophy; heart failure, ischemic diseases; inflammation; autoimmunediseases; AIDS; fertilization and implantation of fertilized ovum;osteopathias such as osteoporosis; brain functional disorder; infectionof digestive tracts with bacteria; sepsis; adult respiratory distresssyndrome; retinopathy; glaucoma; and erectile dysfunction.

1. A method of treating disease through inhibiting Rho kinase, whereinthe disease is selected from the group consisting of hypertension,angina, cerebral vasospasm, asthma, prostatic hypertrophy, blood vesselrestinosis, cardiac hypertrophy, glaucoma, erectile dysfunction, andurinary incontinence, said method comprising administering atherapeutically effective amount of a compound represented by theformula (5):

wherein the groups represented by the formulas R^(1a) and X^(a) are asfollows: (i) R^(1a) is a substituted or unsubstituted alkyl group andX^(a) is a single bond, or (ii) R^(1a) is a carboxyl group, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedcycloalkyl group, a substituted or unsubstituted cycloalkenyl group, asubstituted or unsubstituted alkoxycarbonyl group, a substituted orunsubstituted alkylsulfonyl group, a substituted or unsubstitutedarylsulfonyl group, or a cycloalkyl group substituted by a substitutedor unsubstituted alkyl group, and X^(a) is a group represented by theformula: —O—, —C(═O)N(R³)—, —S(O)_(n)—, —S(O)₂N(R³)— or —C(═O)— R^(1b)is a substituted or unsubstituted cycloalkyl group, or a substituted orunsubstituted cycloalkenyl group; X^(b) is a group represented by theformula: —O—, —N(R³)—, —NHC(═O)—, or —C(═O)NH—, both of the groupsrepresented by the formulas R^(1c)-X^(c) and R^(1d)-X^(d) are hydrogenatoms, provided that when R^(1a) is an unsubstituted alkyl group, thecorresponding X^(a) is not the group represented by the formula:—C(═O)—; R³ is a hydrogen atom, an unsubstituted alkyl group, anunsubstituted cycloalkyl group, or an unsubstituted arylalkyl group, R⁵¹is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group, anunsubstituted alkyl group, an unsubstituted cycloalkyl group, anunsubstituted cycloalkenyl group, an unsubstituted alkoxycarbonyl group,or a group represented by the formula: —OR⁸, —N(R⁹)R¹⁰, —CON(R⁹)R¹⁰,—SO²N(R⁹)R¹⁰ or —S(O)_(m)R¹¹, m is 0, 1 or 2, each of R⁸, R⁹ and R¹⁰,which may be the same or different, is a hydrogen atom, an unsubstitutedalkyl group, an unsubstituted cycloalkyl group, an unsubstitutedcycloalkenyl group, an unsubstituted alkoxycarbonyl group, or anunsubstituted arylalkyl group, R¹¹ is an unsubstituted alkyl group, anunsubstituted cycloalkyl group, an unsubstituted cycloalkenyl group, oran unsubstituted arylalkyl group, and R⁶ is a hydrogen atom, anunsubstituted alkyl group, an unsubstituted cycloalkyl group, anunsubstituted cycloalkenyl group, an unsubstituted alkoxycarbonyl group,or a group represented by the formula: —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or—S(O)_(mR) ¹¹; a prodrug of said compound, or a pharmaceuticallyacceptable salt of said compound or prodrug.
 2. A compound representedby the formula (5):

wherein the groups represented by the formulas R^(1a) and X^(a) are asfollows: (i) R^(1a) is a substituted or unsubstituted alkyl group andX^(a) is a single bond, or (ii) R^(1a) is a carboxyl group, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedcycloalkyl group, a substituted or unsubstituted cycloalkenyl group, asubstituted or unsubstituted alkoxycarbonyl group, a substituted orunsubstituted alkylsulfonyl group, a substituted or unsubstitutedarylsulfonyl group, or a cycloalkyl group substituted by a substitutedor unsubstituted alkyl group, and X^(a) is a group represented by theformula: —O—, —C(═O)N(R³)—, —S(O)_(n)—, —S(O)₂N(R³)— or —C(═O)— R^(1b)is a substituted or unsubstituted cycloalkyl group, or a substituted orunsubstituted cycloalkenyl group; X^(b) is a group represented by theformula: —O—, —N(R³)—, —NHC(═O)—, or —C(═O)NH—, both of the groupsrepresented by the formulas R^(1c)—X^(c) and R^(1d)—X^(d) are hydrogenatoms, provided that when Ria is an unsubstituted alkyl group, thecorresponding Xa is not the group represented by the formula: —C(═O)—;R³ is a hydrogen atom, an unsubstituted alkyl group, an unsubstitutedcycloalkyl group, or an unsubstituted arylalkyl group, R⁵¹ is a hydrogenatom, a halogen atom, a nitro group, a carboxyl group, an unsubstitutedalkyl group, an unsubstituted cycloalkyl group, an unsubstitutedcycloalkenyl group, an unsubstituted alkoxycarbonyl group, or a grouprepresented by the formula: —OR⁸, —N(R⁹)R¹⁰, CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or—S(O)_(m)R¹¹, m is 0, 1 or 2, each of R⁸, R⁹ and R¹⁰, which may be thesame or different, is a hydrogen atom, an unsubstituted alkyl group, anunsubstituted cycloalkyl group, an unsubstituted cycloalkenyl group, anunsubstituted alkoxycarbonyl group, or an unsubstituted arylalkyl group,R¹¹ is an unsubstituted alkyl group, an unsubstituted cycloalkyl group,an unsubstituted cycloalkenyl group, or an unsubstituted arylalkylgroup, and R⁶ is a hydrogen atom, an unsubstituted alkyl group, anunsubstituted cycloalkyl group, an unsubstituted cycloalkenyl group, anunsubstituted alkoxycarbonyl group, or a group represented by theformula: —CON(R⁹)R¹⁰, —SO₂N(R⁹)R¹⁰ or —S(O)_(mR) ¹¹; a prodrug of saidcompound or a pharmaceutically acceptable salt of said compound orprodrug.
 3. A compound, a prodrug thereof or a pharmaceuticallyacceptable salt of the compound or prodrug according to claim 2, whereinthe group represented by X^(a) is a group represented by the formula:—O—.
 4. A pharmaceutical composition comprising a compound, a prodrugthereof or a pharmaceutically acceptable salt of the compound or prodrugaccording to any one of claims 2 to
 3. 5. A compound according to claim2, wherein R⁵¹ and R⁶ are hydrogen atoms; a prodrug of said compound ora pharmaceutically acceptable salt of said compound or prodrug.
 6. Acompound according to claim 2, wherein R^(1b) is a substitutedcycloalkyl group and X^(b) is a group represented by the formula: —O—; aprodrug of said compound or a pharmaceutically acceptable salt of saidcompound or prodrug.
 7. A compound according to claim 2, wherein R^(1a)is a substituted or unsubstituted alkyl group and X^(a) is a single bondor a group represented by the formula: —O— or —S—; a prodrug of saidcompound or a pharmaceutically acceptable salt of said compound orprodrug.
 8. A compound according to claim 2, wherein R⁵¹ and R⁶ arehydrogen atoms; R^(1b) is a substituted cycloalkyl group; and X^(b) is agroup represented by the formula: —O—; a prodrug of said compound or apharmaceutically acceptable salt of said compound or prodrug.
 9. Acompound according to claim 2, wherein R⁵¹ and R⁶ are hydrogen atoms;R^(1a) is a substituted or unsubstituted alkyl group; and X^(a) is asingle bond or a group represented by the formula: —O— or —S—; a prodrugof said compound or a pharmaceutically acceptable salt of said compoundor prodrug.
 10. A compound according to claim 2, wherein R^(1b) is asubstituted cycloalkyl group; X^(b) is a group represented by theformula: —O—; R^(1a) is a substituted or unsubstituted alkyl group; andX^(a) is a single bond or a group represented by the formula: —O— or—S—; a prodrug of said compound or a pharmaceutically acceptable salt ofsaid compound or prodrug.
 11. A compound according to claim 2, whereinR^(1b) is a substituted cycloalkyl group; R^(1b) is a substitutedcycloalkyl group; X^(b) is a group represented by the formula: —O—;R^(1a) is a substituted or unsubstituted alkyl group; and X^(a) is asingle bond or a group represented by the formula: —O— or —S—; a prodrugof said compound or a pharmaceutically acceptable salt of said compoundor prodrug.
 12. A method of treating disease through inhibiting Rhokinase according to claim 1, wherein the disease is urinaryincontinence.